Deniz Yilmaz

Psychosocial implications of Thalassemia Major.

Abstract  Background : Many causes including the chronicity of disease, burden of treatment modalities, morbidities, and the expectation of early death resulting from the disease complications, may lead to psychosocial burden in Thalassemia Major (TM) patients.

Lung Function, Pulmonary Complications, and Mortality after Allogeneic Blood and Marrow Transplantation in Children

Pulmonary complications (PC) remain a significant barrier to the success of allogeneic blood and marrow transplantation (BMT). Pretransplant pulmonary function tests (PFTs) have been correlated with risk of early respiratory failure and mortality in adult BMT recipients. There is limited data on their relationship to posttransplant outcomes in pediatric patients. We sought, in pediatric allo-BMT recipients (1) to analyze the spectrum of infectious and noninfectious PCs, (2) to evaluate the prevalence and course of PFT abnormalities before and after transplant, and (3) to correlate pretransplant PFT findings with patient outcomes, specifically risk of PC, respiratory failure, and death. We conducted a retrospective review of PC in all patients who underwent allo-BMT at Childrens Hospital of Pittsburgh during 1996 to 2006. PFTs were performed in children 6 years and older pretransplant, 3, 6, 12, and 24 months after transplant. PCs occurring within 100 days of BMT were considered early. One hundred ten consecutive children who underwent allo-BMT were included (median age = 9.7 years; 67 males, 43 females). Seventy-five of 110 patients had 370 PFT studies performed; 62 of 73 patients >6 years of age (85%) underwent PFT studies pre-BMT. There was a significantly higher risk of early respiratory failure in patients with reduced pretransplant forced expiratory volume in 1 second (FEV(1)) (P = .0001, odds ratio [OR] 5.1) or forced vital capacity (FVC) (P = .0001, OR 8.5). Forty-three of 110 (39%) patients required mechanical ventilation, and in 30 episodes (70%), patients remained ventilator-dependent until time of death. Posttransplant, we observed statistically significant reductions in FEV(1), FVC, total lung capacity (TLC), and diffusing capacity of the lungs (DLco) at 3 months post-BMT and similar reductions at 6 months post-BMT except for DLco (not significant). Between 12 and 24 months, FEV(1), FVC, TLC, and DLco improved significantly from earlier declines post-BMT; however FEV(1) and FVC remained significantly below pretransplant values. At a median follow-up of 5.5 (1.6-11.6) years, 58 of 110 (53%) patients were surviving. The majority of the patients who died from transplant-related complications suffered from 1 or more PCs (31/32, 97%). Early PC was associated with over 4-fold reduction in probability of survival at 10 years (8/44, 18% with early PC versus 50/66, 76% without early PC). On multivariate analysis, risk of death was significantly associated with high-risk disease status (P = .015; hazard ratio [HR] = 2.5), unrelated donor (P = .03; HR = 2.1), early PC (P = .0001; HR = 7.7) and pathogen identification (P = .02; HR = 2.7). These results suggest that, in children undergoing allo-BMT (1) compromised pretransplant lung function is significantly correlated with risk of early respiratory failure but not of overall survival (OS), (2) reductions in lung volumes and diffusion capacity are common 3- to 6-month posttransplant with partial recovery by 12 to 24 months, (3) there is high mortality following mechanical ventilation, and (4) early PCs are associated with significantly worse OS.

SINGLE-CENTER EXPERIENCE: Use of Recombinant Factor VIIa for Acute Life-Threatening Bleeding in Children without Congenital Hemorrhagic Disorder

Coagulopathy is an important cause of mortality in critically ill children. Traditional therapies to correct coagulopathy lead to great time delays and cause fluid overload in patients. The authors report the effectiveness and safety of the activated recombinant factor VII (rFVIIa) administration in a series of 13 nonhemophiliac children with acute, life-threatening bleeding. In this retrospective study, the records of the patients who were not diagnosed with congenital hemorrhagic disorder and were administered rFVIIa due to any other reason in Ege University Faculty of Medicine, Department of Pediatrics, between February 2002 and February 2007 were reviewed retrospectively. Thirteen nonhemophiliac patients with acute life-threatening bleeding and ages ranging from 2 days to 15 years received rFVIIa over a 5-year period. Three patients were diagnosed with hemaphagocytic lymphohistiocytosis, 4 with prematurity, sepsis, and disseminated intravascular coagulation (DIC), 5 with sepsis, multiple organ dysfunction syndrome, and DIC, and 1 with acute liver failure. Severe bleeding resulted from pulmonary (n = 3), lower gastrointestinal system (n = 2), esophagus varices (n = 1), pulmonary and gastrointestinal system (n = 4), pulmonary, gastrointestinal system, and intracranial hemorrhage (n = 1), and gastrointestinal system and intracranial hemorrhage (n = 2). Median frequency of rFVIIa administration was 3 per patient (range 2–15) and median dose of rFVIIa was 90 μg/kg, ranging from 60 to 135 μg/kg each administration. All of the patients were given fresh frozen plasma and if necessary platelet transfusion (n = 10) or fibrinogen concentrate (n = 3) before administration of rFVIIa. In 6 patients, lack of success to control bleeding by conventional methods was the only cause to start rFVIIa. In 7 patients, the need for volume restriction was also a significant contributing factor in deciding to start rFVIIa. Median PT was 32.9 s (range: 19–65) before rFVIIa administration and it was decreased to 11.6 s (range: 10.7–12.8), 2–3 h after rFVIIa infusion. Bleeding was stopped completely in 10 patients at least for 24 h and decreased in 3 patients 30–45 min after rFVIIa administration. Two patients had thrombotic complications attributed to rFVIIa administration. No other complication was observed in the other patients. In this retrospective study, rFVIIa was found to be effective at controlling severe hemorrhagic symptoms of different etiologies in children without congenital hemorrhagic disorder. In addition to the rapid control of bleeding, administration of this agent improved fluid balance and led to a reduction in blood product requirements in critically ill children. However, survival was still poor (23%), and 2/13 (15.4%) patients developed venous and arterial thrombosis within 3 h of treatment. The authors emphasize that in acquired, acute life-threatening bleeding, simultaneous administration of rFVIIa with conventional treatment may contribute to patient survival. However, the risk of thromboembolism should be considered before this treatment is given.

The elevated markers of hypercoagulability in children with Henoch-Schönlein purpura

Twenty-eight children with HSP and 79 healthy children were entered into study. Activities of protein C, free- protein S and antithrombin, activated protein C resistance, levels of fibrinogen, D-dimer, thrombin-antithrombin complex (TAT), prothrombin fragments 1+2 (PF1 + 2) and von Willebrand factor antigen (vWAg) and its activity (RiCof), were investigated in acute and recovery phases of HSP and controls. Fibrinogen, D-dimer, TAT, PF1 + 2, vWAg and RiCof levels in patients with HSP during the acute phase were significantly higher than those of recovery phase and of the controls. A significant correlation was detected between severity of disease and TAT, PF1+2, vWAg, D-dimer levels.

Sedation with intravenous ketamine and midazolam for painful procedures in children

Background: Children often require relief of pain and anxiety when undergoing painful procedures. The purpose of this study is to evaluate the effectiveness and safety of painful pediatric procedures performed by pediatric intensivist, using the combination of intravenous ketamine and midazolam for sedation and analgesia.

A SINGLE INSTITUTIONAL EXPERIENCE: Is Epoetin Alpha Effective in Anemic Children with Cancer?

The authors aimed to investigate the efficacy of epoetin-alpha on hemoglobin levels and red cell transfusion requirement in children with both hematologic malignancy (HM, n = 27) and solid tumors (ST, n = 14). Epoetin-alpha was given (150 U/kg or 250 U/kg, thrice weekly) for 12 weeks. Epoetin alpha significantly increased the hemoglobin levels at the 2nd and 3rd months of therapy (p <. 05). At the 3rd month, the patients required less red cell transfusion. At the dose of 150 U/kg, only three patients with HM, but none of the ST patients, required red cell. However, none required red cell transfusion after 2nd month on epoetin alpha 250 U/kg. Epoetin-alpha administration increases hemoglobin levels and decreases red cell transfusion requirement in children with malignancy.

SAFETY PROFILES OF Fe2+ AND Fe3+ ORAL PREPARATIONS IN THE TREATMENT OF IRON DEFICIENCY ANEMIA IN CHILDREN

The major purpose of this study was to compare the oxidant-related toxicities of the different oral iron preparations in children with iron deficiency anemia (IDA); the second aim was to investigate the side effects of iron preparations. Seventy-two children with IDA were randomly included in the Fe2+ group (= 39) or the Fe3+ group (= 33). Some oxidizable substrates (erythrocytes malondialdehyde (MDA), urine 8-isoprostane, and basal and Cu-stimulated-oxidized LDL and antioxidant enzyme (superoxide dismutase (SOD), catalase and glutathione peroxidase) activities were evaluated at the beginning and at the 1st, 3rd, and 6th months of therapy. Side effects due to medication were recorded. While at the end of the 1st month SOD levels were significantly increased in Fe3+ group, at the 6th month evaluation, basal-oxidized LDL levels were significantly increased in the Fe3+ group, as was urine 8-isoprostane in the Fe2+ group. No other difference was found between two groups. In conclusion, there were minimal differences between children treated with ferric or ferrous iron in antioxidant system activities, the status of oxidizable substrates, and clinical toxicities.

Antioxidant defense systems in newborns undergoing phototherapy

This paper was designed to investigate whether phototherapy is an oxidative stress in newborn infants undergoing phototherapy. A day-light continuous phototherapy was given to jaundiced 20 term and 16 preterm newborns for 72 hours. We measured serum vitamin E and the activities of red blood cell anti-oxidation enzymes (superoxide dismutase, catalase and glutathione peroxidase) before and after 72 h of phototherapy. Serum vitamin E levels were not different before and after 72 h of phototherapy in both preterm and term infants. In several studies, antioxidant enzyme activities have been shown to increase in response to oxidative stresses. In this study, however, the antioxidant enzyme activities in the hemolysate were similar before and at the end of the phototherapy in both preterm and full term. In conclusion, the results of ourin vivo study do not confirm the thesis that phototherapy is an oxidative stress in newborn infants. Therefore, phototherapy would preferably seem to be safe and efficient method of treatment for all neonates presenting with hyperbilirubinemia.

A novel mutation in the DIA1 gene in a patient with methemoglobinemia type II.

Methemoglobin (MetHb) is the form of hemoglobin in which Fe3þ is present. Fe3þ cannot bind oxygen as Fe2þ can, and MetHb formation therefore results in developing symptoms of decreased oxygen delivery to tissues. Methemoglobinemia is an increase in the concentration ofMetHb in the blood,which is caused by hereditary or acquired factors. The hereditary form results from a deficiency in the enzyme nicotinamide adenine dinucleotide (NADH) cytochrome b-5 reductase, also known as diaphorase 1 (DIA1). This condition is transmitted in an autosomal recessive mode and is called recessive congenital methemoglobinemia (RCM). There are two forms of DIA1, a membrane-bound form and a shorter, soluble form only found in erythrocytes.Both formsare encodedbya single gene (DIA1) on chromosome 22q13. RCM has been clinically classified into two types. In type I, cyanosis is the only clinical symptom. The clinical features of type II are severe and lethal, and associated with neurological and skeletal abnormalities.Mutations in the DIA1 gene may be associated with clinical and biochemical differences between the methemoglobinemia patients [Aalfs et al., 2000; Dekker et al., 2001]. We describe a novel mutation in theDIA1 gene in a patient with methemoglobinemia type II and compare the findings with the other published cases. A 5-year-old male was born to consanguineous parents as a second child. The first child was a female who presented with similar findings as did the index case. The first child died when she was 20-day-old. The second child was 2,500 g and 50 cm at birth. He was noted to have cyanosis shortly after birth.Onadmission at the age of 3 years, hisweightwas9,700 g (<3rd centile) and his height 82 cm (<3rd centile). His head circumference was 42 cm (< 2 SD). He had persistant central cyanosis without cardiac or pulmonary pathology and hypotonia. At the age of 5 years, he could not control his head or sit-up. MetHb concentrations and MetHb reductase activity in the erythrocytes of the index case and his parents are shown in Table I. Treatmentwith ascorbic acid in the index case resulted in decrease of the MetHb concentration to 14.7%. DNA analysis revealed a homozygous replacement of thymidine by cytidine in intron 5 ofDIA1, at theþ2 position from the boundary with exon 5. All exons and flanking sequences were sequenced and no other alteration was found. Both parents were shown to be heterozygotes for this mutation. Methemoglobinemia types I and II are caused by mutations in a single gene (DIA1) on chromosome 22q13, which has nine exons and eight introns. As has been pointed out by Aalfs et al. [2000] and Dekker et al. [2001], methemoglobinemia type II mutations are more often associated with nonsense mutations or deletions. The mutation found in the patient affects the highly conserved GT of the intron 5 splice donor site and probably causes missplicing of the DIA1 mRNA, leading to skipping of exon 5. To date, less than 15 different mutations have beendescribed inmethemoglobinemia type II [Kobayashi etal., 1990; Nagai et al., 1993; Shirabe et al., 1994; Shirabe et al., 1995; Vieira et al., 1995;Manabe et al., 1996;Owen et al., 1997; Aalfs et al., 2000; Kugler et al., 2001]. Clinical features of type II are destructive and most patients die at an early age. The enzyme deficiency in type II is present both in the membranebound and in the soluble form of DIA1, in all tissues. Severe mental retardation, microcephaly, growth retardation, neurologic impairment such as opisthotonus, athetoid movements, strabismus, and hypertonia besides cyanosis have been described inRCM type II [OMIM, 2000]. The patient presented showed almost all the clinical characteristics of type II methemoglobinemia, such as mental retardation, developmental delay, and failure to thrive. Seizures have been also described in those patients, but these were not observed in our patient. It has been suggested that molecular differences that lead to variations in enzymatic characteristics may help to explain the clinical differences between RCM types I and II [Kugler et al., 2001]. Dekker et al. [2001] have described that type I mutations are found in marginal regions of the enzyme, resulting in unstable but enzymatically active proteins, whereas type II mutations cause premature termination of protein synthesis, resulting in the loss of protein expression or formation of inactive protein. The unstable DIA1 protein in

A rescue therapy with a combination of caspofungin and liposomal amphotericin B or voriconazole in children with haematological malignancy and refractory invasive fungal infections.

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5–17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3–69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3–14) days and 91 patient days for LAmB + caspofungin combination and 49 (7–126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve‐week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies.