Outcome of Early Hemostatic Intervention in Children With Sepsis and Nonovert Disseminated Intravascular Coagulation Admitted to PICU: A Randomized Controlled Trial.

OBJECTIVES: Evaluation of the outcome of early hemostatic management of disseminated intravascular coagulopathy in patients with severe sepsis/septic shock admitted to PICU, before the development of clinically overt disseminated intravascular coagulopathy. DESIGN: Prospective interventional, open label randomized controlled clinical trial. SETTING: PICU at Alexandria University Children's Hospital. PATIENTS: The study included 80 patients with proven severe sepsis/septic shock in nonovert disseminated intravascular coagulopathy stage. They were randomly assigned into two groups (group 1 and group 2). INTERVENTIONS: Specific intervention was applied for group 1 (plasma transfusion, low-dose unfractionated heparin, and tranexamic acid). MEASUREMENTS: All patients had assessment of Pediatric Index of Mortality 2 score, Pediatric Logistic Organ Dysfunction score, inotropic score, routine laboratory, and hemostatic tests including fibrin degradation products and d-dimers. Disseminated intravascular coagulopathy risk assessment scores were calculated on daily basis. RESULTS: Mortality rate was significantly higher in group 2. Progression to overt disseminated intravascular coagulopathy was significantly more common among group 2 patients than group 1 (45% and 10%, respectively) (p < 0.0001). Disseminated intravascular coagulopathyRisk Assessment Scores were significantly higher on the second and fifth days among group 2 patients. The initial specific hemostatic intervention was the only significant predictor of survival and prevention of progression to overt disseminated intravascular coagulopathy. CONCLUSIONS: Our results suggest that early use of a combination of fresh frozen plasma transfusion, low-dose heparin, and tranexamic acid in children with severe sepsis/septic shock in the "window of opportunity" before the development of overt disseminated intravascular coagulopathy stage was associated with better outcome for survival and prevention of progression to overt disseminated intravascular coagulopathy, with no increase in bleeding risk. Larger multicenter studies are needed to further prove this practice.

Premature ventricular contractions as a side effect of filgrastim in a child with B-thalassaemia.

Premature ventricular contractions are a rare side effect of filgrastim, reported mainly in elderly men. Here we report the case of a 9-year-old child with thalassaemia who developed frequent premature ventricular contractions after three doses of filgrastim were given for deferiprone-induced agranulocytosis. The arrhythmia resolved 3 weeks after discontinuation of filgrastim. Children treated with filgrastim should be carefully monitored for potentially serious arrhythmia.

Deviating from safety guidelines during deferiprone therapy in clinical practice may not be associated with higher risk of agranulocytosis.

BACKGROUND: A risk associated with the iron chelator deferiprone is the development of neutropenia or agranulocytosis. Accordingly, the product label recommends weekly blood monitoring and immediate interruption of treatment upon detection of an absolute neutrophil count (ANC) <1.5 × 10(9)/L, out of concern that continued therapy might lead to a more severe drop. However, it is uncertain how these recommendations are followed under real-life conditions and, if they are not followed, whether continuation of therapy results in increased incidence of agranulocytosis. PROCEDURE: This non-interventional surveillance program assessed the monitoring of deferiprone therapy in clinical practice. A total of 294 patients with transfusion-dependent anemias received deferiprone, as monotherapy or with another chelator, for up to 1 year. The participating physicians were not given any instructions about treatment and monitoring beyond being referred to the information in the package insert. RESULTS: ANC monitoring was conducted at an average interval of 5 ± 4 weeks, and deferiprone was not always interrupted upon detection of neutropenia. One patient (0.3%) experienced agranulocytosis, and nine others (3%) experienced a total of 11 episodes of neutropenia. All neutropenia episodes resolved; median time to resolution was similar whether or not treatment was interrupted; and no case of neutropenia progressed to agranulocytosis. CONCLUSIONS: These data indicate that less frequent ANC monitoring and continuation of deferiprone therapy during neutropenia are not associated with prolonged neutropenia or with progression to agranulocytosis.

dRTA and hemolytic anemia: first detailed description of SLC4A1 A858D mutation in homozygous state.

Mutations in the anion exchanger 1 (AE1) gene encoding the erythroid and kidney anion (chloride-bicarbonate) exchanger 1 may result in familial distal renal tubular acidosis (dRTA) in association with membrane defect hemolytic anemia. Seven children presenting with hyperchloremic normal anion gap metabolic acidosis, failure to thrive, and compensated hemolytic anemia were studied. Analysis of red cell AE1/Band 3 surface expression by Eosin 5'-maleimide (E5M) was performed in patients and their family members using flow cytometry. Genetic studies showed that all patients carried a common SLC4A1 mutation, c.2573C>A; p.Ala858Asp in exon 19, found as homozygous (A858D/A858D) mutation in the patients and heterozygous (A858D/N) in the parents. Analysis by flowcytometry revealed a single uniform fluorescence peak, with the mean channel fluorescence (MCF) markedly reduced in cases with homozygous mutation, along with a left shift of fluorescence signal but was only mildly reduced in the heterozygous state. Red cell morphology showed striking acanthocytosis in the homozygous state [patients] and only a mild acanthocytosis in heterozygous state [parents]. In conclusion, this is the first description of a series of homozygous cases with the A858D mutation. The E5M flowcytometry test is specific for reduction in the Band 3 membrane protein and was useful in conjunction with a careful morphological examination of peripheral blood smears in our patient cohort.

Breastfeeding is not associated with risk of developing childhood leukemia in the Sultanate of Oman.

BACKGROUND: Recent case-control studies on breastfeeding and childhood leukemia risk have indicated that longer duration of breast feeding (> 6 months) is associated with decreased risk of the disease. OBJECTIVE: To investigate the relationship between duration of breastfeeding and risk of childhood leukemia in Oman. MATERIALS AND METHODS: In a case control study all recently diagnosed and registered cases of childhood leukemia at the National Registry during (1999-2009), a total of 70 cases, were recruited. For each case, a gender and age matched control was selected either from the family relatives or from the neighbors of family siblings. RESULTS: Breastfeeding is culturally favored for longer periods of time (up to 24 months) in Oman. Data of this study revealed that 21% of cases and 12 % of their gender and age matched controls were breastfed for an average duration of 6-12 months. In 75% of the cases and 81% of controls the period of breastfeeding was between 12-24 months. Only 4% of the cases and 7% of controls were breastfed for a period more than 24 months. No significant (P>0.05) differences were observed between the cases and controls with respect to breastfeeding and the risk of childhood leukemia in Oman. Similarly the duration of breast feeding did not have any significant (P>0.05) effect on the risk. CONCLUSION: This study indicated that duration of breastfeeding was not associated with risk of childhood leukemia in Oman and there may be some other environmental and genetic factors that might be responsible for the occurrence of this disease that must be explored further.

Effect of hydroxyurea on physical fitness indices in children with sickle cell anemia.

The current studies aimed at determining physical fitness indices and anthropometrics profiles of children with sickle cell anemia (SCA) after the use of hydroxyurea (HU). Ninety-three male schoolchildren--who participated previously in a similar study before the introduction of HU--comprising 2 groups participated in the studies. Group 1 was 41 children who were suffering from sickle cell disease (SCD) and were on HU for a minimum of 2 years, whereas group 2 was 50 normal healthy controls. Anthropometrics measurement and parameters of physical fitness were assessed in all subjects. All children were also subjected to a minimum of 6-minute running exercise test on a flat motorized treadmill at speed corresponding to 5 km/h. Throughout the test heart rate was monitored and recorded during exercise and for 10 minutes during recovery. Blood hemoglobin (Hb) and HbF% were measured after the use of HU. The mean values of weight, height, and lean body mass were still lower in the SCD children (P < .05) compared with the healthy subjects. However, they had significant decrease in the mean heart rate values and they spent longer time on the treadmill before they got tired compared to their previous performance and were just below the normal controls. Hydroxyurea treatment improved the aerobic exercise tolerance and most of the physical fitness parameters in children with SCD.

A child with human parvovirus B19 infection induced aplastic anemia and acute hepatitis: effectiveness of immunosuppressive therapy.

Human parvovirus B19 (HPV B19) infections are usually asymptomatic or benign and self-limiting. In immunocompromised patients and patients with chronic hemolytic anemia, it can lead to transient red cell aplasia. Few reports in the literature have implicated HPV B19 as the possible cause of acute hepatitis and severe aplastic anemia in immunocompetent patients. Here, the authors report a previously healthy 6-year-old girl with acute hepatitis and severe aplastic anemia associated with HPV B19 infection diagnosed by serology (ELISA). Other common causes of these manifestations were ruled out. The clinical manifestations subsequently improved significantly with the use of immunosuppressive therapy confirming an autoimmune mechanism.

Invasive candidal laryngitis as a manifestation of cyclic neutropenia in an Omani infant.

Cyclic neutropenia is a congenital episodic defect in the development of neutrophils in the bone marrow. It is usually diagnosed late in infancy as it generally takes several cycles of neutropenia before the condition is suspected. These patients often have recurrent mild infectious episodes, but may develop life-threatening bacterial infections; however, they are unlikely to develop fungal infections as the neutropenia is usually self-limiting and of short duration. The authors report the case of an 8-month-old Omani female infant with cyclic neutropenia presenting as severe fungal (Candida) invasive laryngitis, needing life-saving tracheostomy and i.v. antifungal treatment.

Novel spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis in ethnic Omani patients.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive immune disorder, characterized by fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, markedly elevated levels of inflammatory cytokines, and impaired cytotoxic activity of lymphocytes. FHL is often fatal in early infancy. Histologic features include organ infiltration by activated macrophages and lymphocytes. Four genetic loci (FHL1, 2, 3, and 4) have been identified, of which FHL2 involves mutations in the perforin gene and is present in 20-50% of patients with FHL. We herein report the first comprehensive molecular analysis of 16 unrelated cases of FHL in ethnic Omanis. Using direct DNA sequencing analysis in 11 families, seven different mutations were identified in the coding region of the perforin gene, of which five were novel. Perforin gene defects do not seem to be involved in one-third of the cases of FHL in ethnic Omanis.

Physical fitness indices and anthropometrics profiles in schoolchildren with sickle cell trait/disease.

The current studies aimed at determining physical fitness indices and anthropometrics profiles of school children with sickle cell trait (SCT) and sickle cell disease (SCD). Male school children (150) comprising 3 Groups participated in the studies. Group 1 has 50 normal healthy controls, while Groups 2 and 3 each has 50 children who were suffering from SCT and SCD, respectively. Anthropometrics measurement and parameters of physical fitness were assessed in all subjects. All children were also subjected to a 5-min running exercise test on a flat motorized treadmill at speed corresponding to 5 km/hr. Throughout the test, heart rate was monitored and recorded during exercise and for 10-min during recovery. Blood lactate was measured before and 5 min following the completion of test. The mean values of lean body mass and height were lower in the SCD children (P < 0.05) compared with the healthy subjects and SCT individuals. Children with SCD exhibited a higher mean value (P < 0.05) for percent body fat and fat mass than the normal healthy subjects and SCT individuals. Although all groups tolerated well the treadmill exercise protocol, the SCD group exhibited higher (P < 0.05) mean values of heart rate during exercise than those observed in the SCT and normal control children. In addition, SCD children showed higher serum lactate values before and after treadmill exercise compared to the other groups. Children with SCD exhibit high level of adiposity; low level of fitness and their exercise performance appears to be physiologically more stressful as indicated by heart rate and blood lactate concentration responses.

Identification of prognosis markers in pediatric high-risk acute lymphoblastic leukemia.

Gene expression profiling may improve the understanding of the biology behind relapse in pediatric acute lymphoblastic leukemia. Using suppression subtractive hybridization (SSH), cDNA concatenated sequencing (CCS), and reverse transcriptase real-time quantitative polymerase chain reaction (RT-RQ-PCR) on high-risk patient samples with nondeterminant chromosomal translocation, the authors identified 3 genes that were significantly overexpressed in the nonrelapsed patients: the calcium/calmodulin-dependent serine protein kinase (CASK), subunit 2 of the cofactor required for SP1 transcriptional activation (CRSP2), and granzyme K (GZMK). The level of expression of these biomarkers may help identify patients with potentially good prognosis within a group otherwise at high risk of relapse.

Craving for ice and iron-deficiency anemia: a case series from Oman.

Pagophagia, or the practice of consuming ice, is a particular expression of the more general phenomenon of pica. Pagophagia is a complex behavioral phenomenon arising from the interplay of biochemical, hematological, psychological, and cultural factors. This compulsive dietary aberration is observed in many children and pregnant women worldwide. The authors report 3 cases of severe iron deficiency anemia with a serum ferritin level of 2-3 ng/mL, in which the patients were consuming 2 trays and many bags of ice per day. Following treatment with iron therapy, pagophagia spontaneously resolved within 2 weeks. It is a commonly missed problem. Pediatricians should be alert to this phenomena and its association with iron-deficiency anemia.

An inframe perforin gene deletion in familial hemophagocytic lymphohistiocytosis is associated with perforin expression.

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive disease of early childhood manifested by hypercytokinemia and organ infiltration of macrophages and activated lymphocytes, and it is characterized by a fulminant clinical course. The molecular mechanism underlying this disease appears to be a deregulation of apoptosis of activated T cells and macrophages. Approximately 20-40% of patients with familial hemophagocytic lymphohistiocytosis reported worldwide had a perforin gene mutation. We report herein a novel perforin variant in the homozygous state in an Omani boy who was diagnosed 44 days after birth. Sequence analysis of the perforin gene coding region revealed a 12-base pair deletion (codon 284-287) resulting in the deletion of four amino acids in the membrane attack complex domain of the protein. This deletion maintains the reading frame of the perforin mRNA. Both parents were heterozygotes for this molecular defect. Flow-cytometric analysis revealed intracellular perforin expression at the lower end of the normal range in the cytotoxic T cells (CD3+/CD8+) and (CD3+/CD56+) and in around 50% of the natural killer cells (CD3-/CD56+). This is an additional example of a perforin variant which is associated with a significant level of cellular perforin expression and thus confirms that drastic reduction in its expression is not a constant feature in familial hemophagocytic lymphohistiocytosis type 2.

Study of intermittent intravenous deferrioxamine high-dose therapy in heavily iron-loaded children with beta-thalassemia major poorly compliant to subcutaneous injections.

The authors tested the efficacy and safety of intermittent high doses of iv deferrioxamine (DFX) on a twice-weekly basis through an externalized venous catheter on 14 thalassemic children who were heavily iron-loaded and poorly or noncomplaint to subcutaneous DFX. The main reasons for their noncompliance were resistance of the child because of severe local reactions or more than one family member affected, with very high burden on the mother to look after all the affected children. There were 9 males and 5 females and their age range was 7-13 years (mean 10.93 +/- 1.9 years). All patients were given a 48-h continuous iv infusion of DFX 200-240 mg/kg/day (approximately 10 mg/kg/h) every 2 weeks, combined with subcutaneous 10-h infusion of DFX 3 days/week. One month after the start of the intermittent high-dose DFX program, the 24 h urinary iron excretion was 29.1-1.50 mg/kg/24 h (mean 69.7 +/- 32.5 mg/kg/24 h). These values dropped significantly to 29-53 mg/kg/24 h (mean 39.8 +/- 7.9 mg/kg/24 h) 1 year after the study (p <.004) and remained almost the same over the second year (mean 39.07 +/- 6.58 mg/kg/24 h). Serum ferritin levels markedly elevated before the start of high-dose chelation fell steadily during iv high-dose DFX therapy. Mean values were 6215.5 +/- 578.3, 3971.5 +/- 321.6, 2507.2 +/- 131.2, and 1866.5 +/- 110 ng/mL at 0, 6, 12, and 24 months, respectively. No serious side effects were reported. Intermittent high-dose DFX therapy combined with 3 days of subcutaneous DFX is safe and effective in reducing iron stores and improving the compliance of these heavily iron-loaded thalassemic children.

Relapsed acute leukemia in children: Oman experience.

Acute leukemia (AL) is the most common malignancy in children in Oman. It accounts for over one-third of all childhood cancers, most of which (approximately 75%) are acute lymphoblastic leukemia (ALL). Over a decade, a total of 128 cases of childhood acute leukemia have been diagnosed and managed at Paediatric Haematology/Oncology Unit, Sultan Qaboos University Hospital, which is the national referral center of pediatric leukemia cases. A retrospective review of case notes was used to study all children with a diagnosis of acute leukemia from January 1993 to January 2003. All the cases were diagnosed using a bone marrow aspirate with morphological and immunophenotypic classification. Over this period, 24 cases relapsed. They were classified as per BFM group as "very early," "early," and "late" according to the time from diagnosis to first relapse and were divided into isolated bone marrow (BM), extramedullary site, and combined relapse. Sixteen percent of ALL cases and 58.6% of acute myeloid leukemia (AML) cases so far relapsed. Most of the AML cases relapsed very early on in treatment. Eleven patients had combined relapse in BM and extramedullary site (9 in the central nervous system, 1 in the testicles, and 1 in the eye). The overall outcome of these patients is very poor, and only 6 patients out of 24 are still alive. In conclusion, the relapse rates of childhood AL are more or less similar to those of other reports but the overall outcome is very poor. A large majority of the patients in this study are either very early or early relapsers. Future studies including genetic and molecular analysis may be able to explain the difference in clinical outcome of these relapsed AL cases.

Clinical and genetic studies of familial hemophagocytic lymphohistiocytosis in Oman: need for early treatment.

Hemophagocytic lymphohistiocytosis (HLH) embraces the frequently indistinguishable conditions of familial hemophagocytic lymphohistiocytosis (FHL) and virus-associated hemophagocytic syndrome (VAHS). Without therapy FHL is invariably fatal, but successful therapy, including chemotherapy and immunotherapy followed by bone marrow transplantation (BMT), has been presented. To clarify the outcome of HLH in a developing country, with regard to clinical, laboratory, and genetic features, a nationwide study on all patients diagnosed with HLH in Oman during the 5-year period 1997-2001 was performed. In 5 patients and their families, mutational analysis was made. Thirteen patients with HLH were identified, 5 of whom had clinical manifestations of central nervous system involvement at presentation. In none of the patients could an infectious cause be identified. Ten children were referred late in the disease course, and the concern about starting chemotherapy before exclusion of an acute viral infection resulted in delayed treatment in some patients. Two children were started early on the HLH-94-therapy followed by successful BMT in one child. In the successfully transplanted child, the response to intrathecal hydrocortisone appeared to be better than standard therapy with intrathecal methotrexate. Finally, a novel missense mutation in the perforin gene was identified in 2 patients and their family members, causing a transition of proline to threonine at codon 89. Early diagnosis and treatment is important to improve outcome. Intrathecal corticosteroids may be considered, in addition to intrathecal methotrexate, in certain patients. Since the novel perforin mutation has been reported in only 2 patients from Oman, and since similar polymorphism in the sequencing data of the members of their families has been identified, a founder effect is possible in this population.

A comparison of two transfusion regimens in the perioperative management of children with sickle cell disease undergoing adenotonsillectomy.

Adenotonsillar hypertrophy and chronic tonsillitis are common findings in patients with sickle cell disease (SCD). Various preoperative transfusion regimens have been suggested to reduce the population of sickle erythrocytes and correct the anemia, ranging from conservative (correcting the anemia) to aggressive (lowering the level of HbS to less than 30%). A total of 39 patients with SCD were included in the study. They were divided into 2 groups. Fourteen patients in group 1 were assigned aggressive exchange transfusion and 25 patients in group 2 were assigned a conservative (simple) transfusion. The 2 groups were compared for possible operative and postoperative complications. Thirty percent of patients in both groups had postoperative complications. They ranged from mild local infection to acute chest syndrome. Simple transfusion was not associated with higher incidence of complications and resulted in only one-third as many transfusion requirements.

Splenic function in Omani children with sickle cell disease: correlation with severity index, hemoglobin phenotype, iron status, and alpha-thalassemia trait.

The prevalence of functional asplenia in Omani children with sickle cell disease (SCD) has not been previously defined. In this study, the authors aim to compare the natural history of splenic dysfunction in their patients to other reports. The splenic function was studied in 72 Omani patients with sickle cell disease (50 homozygous for hemoglobin S (HbS-S), 11 double heterozygotes for HbS and beta(0)-thalassemia (HbS-beta(0)-thal), 5 HbS-beta(+)-thal, 5 patients with hemoglobin S-D disease, and 1 child with hemoglobin S oman trait) aged 4.8-16 years, using (99m)Tc-labeled tin colloid scintigraphy. The study revealed 4 groups according to their colloid uptake: group I included 20 patients (28%) with normal splenic function; group II, 6 patients (8%) with mild hyposplenism; group III, 20 (28%) with severe hyposplenism; and group IV, 26 (36%) patients with functional asplenia. Overall, more than 60% of them had preserved splenic function. Except for HbS-beta(+) patients, the developmental pattern of hyposplenism was not different among the different Hb phenotypes. Factors associated with preservation of spleen function in these patients were larger splenic size (p < .01), less clinical severity (p < .05), lower MCH (p < .01), higher HbF (p < .001), and presence of alpha-thalassemia trait (p < .05).

Pulsed high-dose dexamethasone therapy in children with chronic idiopathic thrombocytopenic purpura.

The effectiveness of pulsed high-dose oral dexamethasone therapy in children with refractory chronic idiopathic thrombocytopenic purpura (ITP) is evaluated. Thirteen children with severe chronic ITP were enrolled in the study from an outpatient pediatric hematology clinic (ages 2-14 years), 5 boys and 7 girls. They did not maintain a response to other forms of therapy (IVIg, Anti-D, conventional steroids, danazol) and one girl relapsed after splenectomy. Dexamethasone was administered orally at a dosage of 40 mg/M2/day (maximum 40 mg/day) for 4 consecutive days. The cycle was repeated once a month for 6 months. The immediate response to therapy was excellent as the mean platelet count at day 1 was 15 x 10(9)/L, while mean platelet count at day 4 was 158 x 10(9)/L. At the end of 6 cycles 3 patients maintained a platelet count of >150 x 10(9)/L and 4 patients showed partial response. At the end of the first year and second year (12 and 24 months after onset of treatment) 3 patients still had complete response, 3 patients had partial response, and 7 patients were failures. Six of the failures underwent splenectomy and one was shifted to dapsone, had no response, and refused splenectomy. Side effects were tolerable. They included bloating, nausea, vomiting, insomnia, anxiety, and depression, and transient glucosuria; however, they were not severe enough to discontinue the cycles. Mean duration of illness prior to start of dexamethasone was not significantly different in between responders and nonresponders. Dexamethasone given orally in high doses is an effective drug in achieving short-term platelet responses. Long-term remission is obtained in nearly half the patients with well-established chronic ITP. Its effectiveness in almost half the patients, minimal side effects, and low cost indicate that this treatment should be considered in patients with chronic ITP who do not tolerate the disease well before considering splenectomy.