effect of hydroxyurea in the management of Pediatric Sickle cell patients

Low levels of fetal hemoglobin [HbF] in sickle cell disease [SCD] patients [pts] are associated with a variety of vaso-acciusive complications and an increased risk of early death. Raising HbF levels can reduce the effect of the disease. Hydroxyurea [HU] reduces the production of HbS containing red cells and favours the production of HbF containing red cells. It has been used successfully in the management of adults with SCD and there is growing data on its efficacy and safety in pediatric age group. This study reviews our clinical experience with HU in the treatment of pediatric pts with SCD attending the Pediatric Hematology Clinic of Cairo University. Sixty SCD pts from 2001 to 2007 who received HU over the period of 6 years [yrs] and who continued therapy for at least 6 months were included. Four pts were excluded because of noncompliance to treatment. Response to HU was assessed both clinically and by laboratory findings. Pts were considered responders if they showed >/= 50% improvement in clinical and laboratory data. These data included number of blood transfusions/yr, vasoocciusive crisis [VOC]/yr requiring admission to the emergency unit, hospital admissions/yr. Laboratory data included Hb [g/dl], MCV [fl], HbF%, total leucocytic count [TLC], x10[3]ml absolute neutrophil count [ANC], platelets x10[3]ml and reticulocytic count [%] and serum ferritin level [ng/ml]. Fifty six pts [44 children and 12 adults [>18 yrs] were included. Their mean age was 14.05 +/- 5.3 yrs [range of 6-28 yrs]. Thirty seven were females and 19 males. Twenty four [42.9%] were sickle-beta thalassemia while 32 [57.1%] were homozygous sickle cell anemia [SS]. The main indications for starting HU therapy were frequent VOC, transfusion dependency and acute chest syndrome [91%, 86% and 16% respectively]. Other indications included hepatic crisis [5%], bone infarction [7%], sequestration crisis [5%] and pulmonary hypertension in one case. HU was started in a dose of 15mg/kg/day with careful monthly monitoring for side effects. There was no attempt to achieve maximum tolerated dose. Dose increase or decrease was done depending on clinical and laboratory response with a maximum dose of 30mg/kg/day. The mean dose of HU was 15.8mg/kg/day [range 10-30 mg/kg/day] and the mean duration of therapy was 3.25 yrs [range of 0.5-6 yrs]. Forty four pts [78.6%] were found to be responders. There was a significant [p<0.05] improvement in all clinical parameters. Responders showed a significant decrease in TLC, ANC, reticulocytic count and serum ferritin [P values 0.002, 0.019, 0.000, 0.001 respectively]. Significant increase in HbF and MCV [p=0.000, 0.001 respectively] was also observed. HU toxicity was defined by>3 fold increase in ALT, platelet count<80,000 p1, ANC<1500 or increase in serum creatinine>50%above baseline. Twenty pts [35.7%] showed signs of HU toxicity: elevated ALT [n=9], neutropenia [n=7], thrombocytopenia [n=1], unexplained jaundice [n=1] and both neutropenia and jaundice [n=2]. Thirteen pts continued therapy with reduction of the dose or temporary stopping of HU while 7 stopped HU. It was noticed that all pts who developed hepatotoxicity were HCV positive p=0.036]. It was also shown that hepatotoxicity was significantly higher among those receiving Deferiprone with HU [n=20] [p=0.001]. There was no relation between response to HU and patients' age, sex, spleen status or phenotype. HU provides the best available strategy to achieve clinical and hematological improvement in SCD in pediatrics, but requires periodic monitoring of blood count and ALT levels especially for HCV positive pts and those on Deferiprone therapy

Flow-cytometric assessment of paroxysmal nocturnal hemoglobinuria clones in pediatric bone marrow failure syndromes

Patients suffering from bone marrow failure might develop various clonal complications, one of which is paroxysmal nocturnal hemoglobinuria [PNH]. We investigated the frequency of development of PNH in acquired aplastic anemia and Fanconi anemia using sensitive flow cytometric method, aiming to detect CD59 deficient expression on granulocytes. We found abnormal expression of CD59 [i.e. PNH clones] in 30.6% of the studied cases. All of them were PNH negative by the less sensitive laboratory methods [Ham's test]. Clinical and laboratory comparison revealed statistically significantly high mean corpuscular volume [MCV=105 +/- 10] in PNH positive patients, while PNH negative patients [MCV was 91 +/- 23. P-value=0.013]. The total leucocytic count was significantly lower in PNH positive' patients [2.9 +/- 1.4] when compared with PNH negative [4.6 +/- 2, P-value = 0.01]. Subgroup analysis revealed that MCV was higher in PNH positive acquired aplastic anemia [AAA] in support to previously stated hypothesis about the relationship between immune etiology and PNH in AAA. Fanconi PNH positive patients were lower in their total leucocytic count indicating more severe form of the disease. In conclusion, we found that Flow cytometric analysis is superior to the Ham test in diagnosis of paroxysmal nocturnal hemoglobinuria. Further follow up of patients with PNH positive clones and their response to various therapeutic modalities is recommended

Recent insight about anti-hepatitis C antibodies in pediatric thalassemia major and sickle cell anemia patients

Hepatitis C virus is a major health care problem in Egypt. One of its high risk groups are multi-transfused children suffering from chronic hemolytic anemia. In the current study we aimed to investigate the prevalence of hepatitis C virus status [HCV] in thalassemia major and sickle cell anemia patients who are regularly following at the pediatric hematology clinics, Cairo University. We also aimed to compare the current prevalence with previous studies conducted before the introduction of donor screening for HCV and so determine the effectiveness of screening currently in use. Two hundred and eighteen children were enrolled in the study. Most of them were thalassemia cases [n=168], while fifty were sickle cell disease patients. The study also included twenty healthy age- matched control to determine the base line risk in the general population. All patients and controls were investigated for the presence of HCV antibody using fourth generation ELISA techniques. The results showed that the over all HCV sero-prevalence rate was 40.5% in thalassemia patients and 50% in sickle cell disease patients, a much lower rate than previously reported before the era of donor screening. The risk for HCV infection in both thalassemia and sickle cell anemia increased with increased duration of transfusion. The mean transfusion duration in HCV positive thalassemia patients was [10.28 +/- 6 years] while among sero-negatives it was [3.27 +/- 4.32 years]. In sickle cell anemia group, the mean duration of transfusion was [7.04 +/- 4.29 y] among HCV positives versus [3.38 +/- 3 y] among HCV negatives and the relation was also highly significant. Serum ferritin was a significantly elevated in HCV positive cases both in sickle and thalassemia patients. The frequency of HCV infection has moderately declined since the introduction of blood screening techniques, however the current prevalence is still high and more efforts are needed to introduce new techniques that avoid the window gap and increase the sensitivity of used techniques. The duration of blood transfusion and high levels of serum ferritin were identified as possible risk factors for HCV infection in the studied groups

Thalassemia intermedia and prevalence of anti-hepatitis C antibodies and other hepatitis markers

This study aimed to find out the prevalence of anti-hepatitis C virus antibodies [anti-HCVAb] and hepatitis B virus [HBV] markers in children with TI and their relation with age, sex, the number of blood units transfused and ferritin level in addition to determining the infection's effects or liver functions. Twenty-eight patients [13 males and 15 females] suffering from TI with a mean age 11.7 +/- 4.9 years were compared with 15 healthy children of the same age and sex. Complete blood count, hemoglobin electrophoresis, liver and kidney functions tests and ferritin level were done in addition to assessment of anti-hepatitis C antibodies [anti-HCVAb], hepatitis B surface antibodies [anti-HBcAb] by ELISA technique. In conclusion, HCV infection might be the cause of morbidity among the occasionally blood transfused thalassemia inter- media patients, even with their low rate of transfusion and even after the introduction of procedures to screen blood products for HCV. Egyptian blood donors should be effectively screened for anti-HCV and individuals who have a history of drug abuse should be deferred from donating the blood. This and stringent infection-control measures are necessary steps to limit the spread of HCV, HBV and perhaps other viruses to patients

Evidence of diastolic Dysfunction and pulmonary hypertension in sickle cell anemia: possible role of L-carnitine treatment

The aim of this work was to assess cardiac status and pulmonary blood pressure in Egyptian sickle cell disease [SCD] pediatric patients. Possible role of L-carnitine in the amelioration of heart complications was also studied. This study was conducted on 37 pediatric patients with sickle cell disease, their mean age was 9.4 +/- 3.6 years. They were subjected to complete history taking, general examination, laboratory investigations [complete blood count and serum ferritin] and echocardiographic examination including measurement of cardiac chamber dimensions, systolic and diastolic functions of left ventricle and estimation of pulmonary artery systolic pressure [PASP]. The echocardiographic findings showed a significant increase in left atrial dimensions in SCD patients compared with the normal controls, which decreased after L-carnitine therapy but did not reach a significant difference. Other cardiac dimensions revealed no significant difference between the patients and control group. Systolic functions of left ventricle did not show any significant difference between patients and controls. Diastolic dysfunction was found in all patients. Diastolic parameters revealed a significant improvement by a decrease in E-wave peak velocity and E/A ratio after L-carnitine therapy. Pulmonary hypertension was found in 17 cases and showed a significant decrease after L-carnitine therapy. The clinical and laboratory re-evaluation of the patients after the period of therapy revealed a significant increase in weight and height of the patients together with a significant decrease in the frequency of blood transfusion and serum ferritin levels