Poorer outcome of childhood acute lymphoblastic leukemia in the Bedouin population: A report from the Berlin-Frankfurt-Muenster-based Israeli national protocols.

BACKGROUND: Therapy outcomes for childhood acute lymphoblastic leukemia (ALL) had substantially improved in the last decades, but variability across racial and ethnic groups was identified in some clinical studies. In this study, we aimed to investigate whether such a difference in outcome is found in the diverse ethnicities in Israel as well. METHODS: A retrospective study was conducted among 1154 patients (855 Jews, 195 Muslims, 52 Bedouins, 26 Druze, and 26 others) aged 1 to 21 years, who were diagnosed with ALL between 1989 and 2011 and were treated according to the same Berlin-Frankfurt-Muenster-based Israel National Study protocols. RESULTS: Bedouins had a higher incidence of t(1;19) (16% vs 3% for non-Bedouins) and a lower incidence of high-hyperdiploidy (10% vs 25% for non-Bedouins) (P = 0.01). Five-year event-free survival (EFS) and overall survival (OS) were poorer for the Bedouins (60.3% ± 7.2% and 63.1% ± 7.2%, respectively) compared with the Jews, Muslims, and Druze (80.4% ± 1.4%, 77.3% ± 3.2%, and 84% ± 7.3%, respectively, for EFS [P = 0.02], and 86.3% ± 1.2%, 82.3% ± 2.9%, and 88.3% ± 6.4%, respectively, for OS [P = 0.002]). Adherence to intensive chemotherapy was similar between the Muslims and the Bedouins. CONCLUSIONS: Our findings suggest that the Bedouins, a highly inbred ethnic Arab people, may be considered a higher risk group that may need more intensive chemotherapy and/or supportive care in order to improve their outcome.

Anemia associated with acute infection in children: an animal model.

BACKGROUND: We constructed an animal model to examine the possibility that erythrophagocytosis may contribute to decreased hemoglobin (Hgb) levels in acute infection in mice. METHODS: BALB/c mice weighing 20 to 25 g were injected (intraperitoneally) with lipopolysaccharide (LPS) (Escherichia coli serotype) of some concentrations. Control mice were injected intraperitoneally with saline (0.5 mL). Two and 4 hours after LPS administration, mice were bled (0.25 mL) for complete blood count measures and tumor necrosis factor-α and interleukin-6 levels. The mice were then killed, and their spleen, liver, and bone marrow were examined microscopically for erythrophagocytosis. RESULTS: After LPS administration, mouse Hgb and hematocrit levels dropped significantly. At 4 hours after LPS injection, all Hgb and hematocrit concentrations were found to be significantly lower compared with that of controls (P = 0.002 and 0.001, respectively). Significantly increased concentrations of tumor necrosis factor-α and interleukin-6 were evident after LPS injection. Prominent hepatic erythrophagocytosis was observed in the LPS-injected mice compared with controls. A significant across-group difference was observed at 4 hours, driven by significantly higher values in group 500 mcg versus controls (P = 0.005) and 100 mcg (P = 0.025). A significant increase in erythrophagocytes was observed at 2 to 4 hours in the 500 mcg LPS group (P = 0.044). CONCLUSIONS: Erythrophagocytosis may play a role in anemia associated with acute infection in mice.

Anemia associated with acute infection in children.

BACKGROUND: The pathogenesis of anemia associated with acute infection in children has not been well delineated. OBJECTIVES: To characterize this type of anemia in children with acute infection, mainly in relation to iron status. METHODS: These two cross-sectional studies compared the prevalence and severity of anemia between outpatient febrile children and age-matched non-febrile controls. RESULTS: In part 1 of the study, children with acute infection (n = 58) had a significant decrease in hemoglobin levels compared with 54 non-febrile controls. Mean corpuscular volume (MCV) did not change this association. Moreover, there was no significant difference in MCV, mean cell hemoglobin or red cell distribution width values between the two groups. Regarding part 2, of the 6534 blood counts obtained in community clinics, 229 were defined as "bacterial infection." Chart survey confirmed this diagnosis. White blood cell level was significantly inversely associated with hemoglobin level (r = -0.36, P < 0.0001). Anemia was significantly more prevalent among children with bacterial infection compared to those without: 21.4% vs. 14.1% (P = 0.002). Mean values of iron status parameters were all within normal limits. CONCLUSIONS: Acute illness is associated with anemia. The pathogenesis of this anemia does not appear to be associated with disruption of iron metabolism.

Hypertonic saline and acute wheezing in preschool children.

BACKGROUND: Most acute wheezing episodes in preschool children are associated with rhinovirus. Rhinovirus decreases extracellular adenosine triphosphate levels, leading to airway surface liquid dehydration. This, along with submucosal edema, mucus plaques, and inflammation, causes failure of mucus clearance. These preschool children do not respond well to available treatments, even oral steroids. This calls for pro-mucus clearance and prohydration treatments such as hypertonic saline in wheezing preschool children. METHODS: Randomized, controlled, double-blind study. Forty-one children (mean age 31.9 ± 17.4 months, range 1-6 years) presented with wheezing to the emergency department were randomized after 1 albuterol inhalation to receive either 4 mL of hypertonic saline 5% (HS) (n = 16) or 4 mL of normal saline (NS) (n = 25), both with 0.5 mL albuterol, twice every 20 minutes in the emergency department and 4 times a day thereafter if hospitalized. The primary outcome measured was length of stay (LOS) and the secondary outcomes were admission rate (AR) and clinical severity score. RESULTS: The LOS was significantly shorter in the HS than in the NS group: median 2 days (range 0-6) versus 3 days (range 0-5) days (P = .027). The AR was significantly lower in the HS than the NS group: 62.2% versus 92%. Clinical severity score improved significantly in both groups but did not reach significance between them. CONCLUSIONS: Using HS inhalations significantly shortens LOS and lowers AR in preschool children presenting with an acute wheezing episode to the emergency department.

Steroid therapy may be effective in augmenting hemoglobin levels during hemolytic crises in children with hereditary spherocytosis.

BACKGROUND: The course of hereditary spherocytosis (HS) may be subject to hemolytic episodes, sometimes requiring blood transfusion. The aim of this study was to evaluate the efficacy of a short course of steroid therapy in elevating hemoglobin levels during hemolytic crisis. PROCEDURE: The files of all patients followed for HS from 1968 to 2009 at our hospital were reviewed. Outcome of hemolytic crises was compared between steroid-treated and untreated patients; patients given packed red blood cell transfusion(s) or erythropoietin treatment were excluded. A good outcome was defined as an increase of at least 20% in hemoglobin level from the nadir within 1 week. RESULTS: Of the 118 patients with HS who attended our hospital during the study period, 20 were treated with steroids and 9 received no treatment. Mean nadir hemoglobin level in both groups was 6.9 g/dl. The study group had a total of 50 steroid-treated hemolytic crises of which 37 (74%) responded favorably to treatment. Treatment failure was significantly associated with a low dose (<1 mg/kg/day) or short duration (<1 week) of treatment. The nine untreated patients had 16 hemolytic crises, of which 25% had a good outcome. Steroid therapy was significantly more effective than no therapy in increasing hemoglobin level (P = 0.015) in these hemolytic crises. CONCLUSION: Steroid therapy may be effective in augmenting hemoglobin levels during hemolytic crises in patients with moderate HS and eventually will result in a reduced need for RBC transfusion.

Anemia of acute infection in hospitalized children-no evidence of hemolysis.

The objective of the study is to examine the assumption that a process of hemolysis plays a role in anemia of acute infection in children. The study was comprised of febrile pediatric patients, who had a positive blood or urine culture. Complete blood count measures were compared between hospitalization and prehospitalization or posthospitalization values. Children admitted to the hospital for elective surgical procedures served as controls. Blood parameters of hemolysis were investigated in some of the patients. Of the 70 patients studied, 49 (70%) were diagnosed with pyelonephritis and 21 (30%) had bacteremia. Mean (+/-SD) hemoglobin (Hgb) on hospital admission was 10.9+/-1.27 g/L as compared with 12.1+/-1.03 g/L of the controls, P<0.0001. Compared with normal-for-age Hgb values as a standard, 42 (60%) cases were identified as anemic. Compared with hospitalization values, Hgb and hematocrit (Hct) were significantly higher in prehospitalization or posthospitalization, whereas WBC values were significantly lower. All parameters of hemolysis, namely reticulocytes, bilirubin, lactate dehydrogenase (LDH), and haptoglobin, were normal. Bacteremia and pyelonephritis are accompanied by a significant drop in Hgb level. There is no evidence of hemolytic anemia in these patients.

Extended triple intrathecal therapy in children with T-cell acute lymphoblastic leukaemia: a report from the Israeli National ALL-Studies.

Owing to the increased central nervous system (CNS) relapse risk in T-cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders - medium-risk (MR) group, accounting for 76% of T-ALL patients. From 1989 to 2003, 143 T-ALL patients aged 1-18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL-Berlin-Frankfurt-Munster (BFM) 86/90 and ALL-BFM 95 protocols, respectively. Five-year event-free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 +/- 5.9% and the INS 98 (n = 43), 83.7 +/- 5.6% (P = 0.12); the cumulative incidence (CI) of any CNS relapse was 5.0 +/- 2.8% and 2.3 +/- 2.3% (P = 0.50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) >or=100 x 10(9)/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T-ALL patients, 5-year EFS was 61.9 +/- 5.3% in INS 89 and 72.9 +/- 5.8% in INS 98, (P = 0.21); the CI of any CNS relapse was 7.1 +/- 2.8% and 1.7 +/- 1.7% (P = 0.142), respectively. Outcome of T-ALL MR patients given extended TIT in the context of BFM-based protocols with long-term follow-up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

Reducing blood transfusion requirements in preterm infants by a new device: a pilot study.

OBJECTIVE: To test a new device designed to salvage red blood cells (RBCs) from blood samples drawn from preterm infants, with the intent of decreasing blood loss and lowering the requirements for RBC transfusions. DESIGN: A case-controlled pilot study was conducted in two Israeli neonatal intensive care units in large municipal hospitals. Twenty low-birthweight preterm infants were randomly and equally divided into the ErythroSave group or a control group. All blood tests in the study group (except for complete blood count and coagulation parameters) were obtained during the first week of life by the new device in the study group and by ordinary syringes in the control group. The main outcome measure was the total number of units of blood needed. RESULTS: The average volume of blood obtained for laboratory analyses from each infant was 27 mL in the ErythroSave group and 24 mL in controls (not significant). The average volume of transfused packed cells was 6.4 mL for the ErythroSave group and 21.3 mL for the controls (p = 0.008). CONCLUSION: The use of ErythroSave for sampling blood significantly reduced blood transfusion requirements in premature infants compared to sampling by conventional syringes.

Age-related leukocyte and cytokine patterns in community-acquired bronchopneumonia.

BACKGROUND: Community-acquired bronchopneumonia in children is frequently accompanied by extreme leukocytosis, whereas in adults with the same diagnosis a high leukocyte count is uncommon. Data regarding differences in the serum levels of inflammatory cytokines between children and adults are limited. OBJECTIVES: To compare leukocyte counts and blood levels of various inflammatory cytokines in children and adults diagnosed with community-acquired bronchopneumonia. METHODS: We prospectively evaluated all pediatric and adult patients admitted for bronchopneumonia based on clinical and chest X-ray findings. Blood was drawn for complete blood count and serum concentration of the following cytokines: granulocyte colony-stimulating factor, interleukins-6, 8 and 10, interferon-gamma, tumor necrosis factor, as well as matrix metalloproteinase-9 and intercellular adhesion molecule-1. RESULTS: There were 31 children and 32 adults. The patients in both groups had similar parameters of infection severity. None of them required admission to the Intensive Care Unit. Mean (+/- SD) leukocyte counts in the pediatric and adult groups were 21,018/mm3 (+/- 10,420) and 12,628/mm3 (+/- 6735) respectively (P = 0.02). Age was inversely correlated with leukocytes in the pediatric group (P = 0.0001). A significant inverse correlation was also found between age and platelet counts. Although cytokine levels in both groups were not significantly different, age was directly correlated with MMP-9 (P= 0.03), IL-8 (P= 0.03) and G-CSF (P= 0.014). CONCLUSIONS: The immune response in community-acquired bronchopneumonia is, at least partly, age-dependent.

Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2 years experience.

BACKGROUND: We recently published preliminary evidence on the effectiveness of hypertonic saline in infants with viral bronchiolitis. OBJECTIVE: To further establish the efficacy of nebulized hypertonic saline in these infants. METHODS: In a continuing, second-year randomized, doubleblind controlled trial, an additional 41 infants (age 2.6 +/- 1 months) hospitalized with viral bronchiolitis were recruited during the winter of 2001-2002. The infants received inhalation of 1.5 mg epinephrine dissolved either in 4 ml normal (0.9%) saline (Group I, n=20) or 4 ml hypertonic (3%) saline (Group II, n=22). The therapy was repeated three times daily until discharge. Pooling our 2 years of experience (2000-2002), a total of 93 hospitalized infants with viral bronchiolitis were recruited; 45 were assigned to Group I and 48 to Group II. RESULTS: The clinical scores at baseline were 7.6 +/- 0.7 for Group I vs. 7.4 +/- 1.3 for Group II (P = NS). However, the clinical scores at days 1 and 2 after inhalation differed significantly between the two groups, invariably favoring Group II: 7 +/- 1 vs. 6.25 +/- 1.1 (P< 0.05), 6.45 +/- 1 vs. 5.35 +/- 1.35 (P< 0.05), respectively. Adding aerosolized 3% saline to 1.5 mg epinephrine reduced the hospitalization stay from 3.5 +/- 1.7 days in Group I to 2.6 +/- 1.4 in Group II (P< 0.05). The pooled data of both years revealed that adding 3% saline to the inhalation mixture decreased hospitalization stay from 3.6 +/- 1.6 to 2.8 +/- 1.3 days (P< 0.05). CONCLUSIONS: This second-year experience and our 2 year pooled data analysis strengthen the evidence that the combination of 3% saline/1.5 mg epinephrine benefits hospitalized infants with viral bronchiolitis.

Aerosol delivery in respiratory syncytial virus bronchiolitis: hood or face mask?

OBJECTIVES: To compare the utility of the hood versus the face mask for delivery of inhaled medications to infants hospitalized with viral bronchiolitis. STUDY DESIGN: Randomized, double-blinded, controlled trial; 49 hospitalized infants with viral bronchiolitis, age 2.75 +/- 2.2 months (mean +/- SD), were grouped to either the hood (n = 25) or the mask (n = 24). Each subject received inhalation treatments with the use of both devices. Half of the Hood Group received the active drug treatment (1.5 mg epinephrine in 4 mL saline [3%]) via hood followed immediately by placebo treatment (normal saline) via mask, whereas the other half received the opposite order. Half of the Mask Group received the active drug treatment via mask followed immediately by placebo treatment via hood, whereas the other half received the opposite order. Therapy was repeated 3 times daily until discharge. Outcome measures included clinical scores and parental preference. RESULTS: Percent improvement in clinical severity scores after inhalation was significant in both groups on days 1, 2, and 3 after admission (Hood Group: 15%, 15.4%, and 16.4%, respectively; Mask Group: 17.5%, 12.1%, and 12.7%, respectively; P < .001). No significant difference in clinical scores improvement between groups was observed. Eighty percent (39/49) of parents favored the hood over the mask; 18% (9/49) preferred the mask and 2% (1/49) were indifferent. CONCLUSIONS: In infants hospitalized with viral bronchiolitis and in whom aerosol treatment is considered, aerosol delivery by hood is as effective as by mask. However, according to parents, the tolerability of the hood is significantly better than that of a mask.

Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease.

BACKGROUND: The clinical spectrum of respiratory syncytial virus (RSV) bronchiolitis in previously healthy infants is extremely variable. Thus, it is likely that factors such as genetic heterogeneity contribute to disease severity. Toll-like receptor 4 (TLR4) and CD14 are part of a receptor complex involved in the innate immune response to RSV. METHODS: The association of the TLR4 mutations (Asp299Gly and Thr399Ile) and the CD14/-159 polymorphism were analyzed in 99 infants hospitalized with severe RSV bronchiolitis (group I). Eighty-two ambulatory infants with mild RSV bronchiolitis (group II) and 90 healthy adults (group III) composed the 2 control groups. The TLR4 mutations and the CD14/-159 polymorphism were genotyped by use of reverse-transcriptase polymerase chain reaction and restriction fragment-length polymorphism analysis, respectively. RESULTS: Each of the TLR4 mutations, either alone or in cosegregation, were associated with severe RSV bronchiolitis: the Asp299Gly and Thr399Ile mutations were significantly overrepresented in group I, compared with groups II and III. No association between the CD14/-159 polymorphism and RSV bronchiolitis was found. CONCLUSIONS: These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.

Cytokine profile in cerebrospinal fluid of children with echovirus type 4 meningitis.

Cytokines play a role in meningeal inflammation and leukocyte recruitment. Research has demonstrated that levels of different cytokines are elevated in aseptic and viral meningitis. Unfortunately, previous data were confounded by the inclusion of multiple viral agents as a study group. The aims of the study were to determine the cerebrospinal fluid concentrations of various cytokines in an outbreak of a single viral agent and to correlate between cytokine levels and leukocytes. Cerebrospinal fluid samples, collected during an outbreak of echovirus type 4 meningitis in infants and children in Israel, were tested for routine characteristics. In addition, cytokine levels were measured in 71 meningitis patients and compared with those of 11 nonmeningitis patients. Concentrations of interleukin-6 (2417 +/- 2713 vs 28 +/- 20 pg/mL; P < 0.01) and interferon gamma (36 +/- 38 vs 4.8 +/- 0.9 pg/mL; P < 0.01) were significantly higher in patients with meningitis than in the control group, whereas soluble intercellular adhesion molecule-1 (1.12 +/- 2.6 vs 0.06 +/- 0.1 ng/mL) levels did not differ significantly. In addition, only interleukin-6 levels correlated with leukocyte counts in viral meningitis patients. Interleukin-6 was the most sensitive and specific characteristic in predicting meningitis in this homogeneous group of patients. Furthermore, only interleukin-6 correlated with leukocyte counts in the cerebrospinal fluid.

The pattern of sesame sensitivity among infants and children.

Recently, we found sesame to be a major cause of severe IgE-mediated food allergic reactions among infants and young children in Israel. The purpose of this study was to describe the different patterns of sesame sensitivity. We have identified three subgroups among our patients (n = 32). Group I (n = 23, M/F; 14/9) consisted of cases with IgE-mediated sesame allergy. The mean age of the first allergic reaction was 11.7 months. Although the main clinical manifestation was urticaria/angiedema (n = 14, 60%), anaphylaxis was the presenting symptom in seven (30%) patients; all of them were younger than 1 year. Sixteen (70%) were found to be allergic to other foods, and other atopic diseases were identified in 18 (78%) patients. Three patients 'outgrew' their allergy within 1-2 years. Group II (n = 2) included cases in whom sesame allergy was ruled out based on a negative skin prick test (SPT) together with a negative open oral challenge. Group III (n = 7) consisted of patients that were found to be SPT positive for sesame as part of a screening for other food allergies. Although sesame products have become fashionable in westernized countries, early exposure may cause sesame to share eventually the same 'noteriety and fate' as peanut - a major cause of severe food allergic reactions.

Use of quantitative ultrasound to assess osteopenia in children with Crohn disease.

BACKGROUND AND AIMS: Children with Crohn disease are at increased risk for osteopenia and osteoporosis. Early development of osteopenia can increase the lifetime risk for fractures and may be amenable to early intervention. The gold standard for measuring bone mineral density (BMD) and fracture risk is dual x-ray absorptiometry (DXA), but this involves some radiation and specialized programs for measuring BMD in children. Bone density Z scores were evaluated with quantitative ultrasound (QUS) using a novel portable device and were compared with DXA in children with Crohn disease. METHODS: Thirty-five children with documented Crohn disease (mean age 14.3 +/- 2.3 years) had speed of sound measured at the left radius and left tibia. Normative values for QUS Z scores were calculated from a cohort of 1,110 healthy children. A subgroup of 26 children with Crohn disease underwent both QUS and DXA. Z scores were calculated and compared for both groups. RESULTS: The mean Z score using lumbar spine DXA was -1.04 +/- 1.51 SD, compared with -0.15 +/- 1.49 SD, using the lowest Z score for QUS ( < 0.05). Using height adjusted DXA, 50% of children with Crohn disease had osteopenia, whereas QUS detected only 19.2% of these children ( < 0.05). Significantly fewer cases of osteopenia were detected using QUS at Z scores up to -2 SD. CONCLUSIONS: Quantitative ultrasound performed on the radius and tibia may not be sensitive enough to pick up osteopenia in children with Crohn disease.

Low compliance of iron supplementation in infancy and relation to socioeconomic status in Israel.

OBJECTIVE: To evaluate the compliance of parents in purchasing iron-containing drugs for their infants. In addition, we looked for possible socioeconomic characteristics of the parents who prevent their infants from accessing these medications. DESIGN: All infants (4-12 months) whose parents bought (from January to August 1999 and from January to August 2000) the iron-containing drugs as recommended by the Israeli Ministry of Health were retrieved from a database. The socioeconomic status of the citizens was determined according to the "mean real income" (INCMV) and "relative income" (INCMS). The percentage of parents who purchased the medication from each district was compared with the socioeconomic status of this population. RESULTS: Forty-four pediatricians' offices in the Tel Aviv metropolitan area were included. The data of 4929 infants was summarized. Only 27% of the parents bought the drugs. Only 11.5% to 20% of parents from the 5 highest socioeconomic classes purchased the medication compared with 43.6% to 57.1% of the parents from the 5 lowest socioeconomic classes. CONCLUSION: There was low compliance by parents in obtaining iron-containing medications for their infants, mainly among parents from high socioeconomic classes.