Allergic Reactions to E. coli Asparaginase are Associated with Decreased Asparaginase Activity in an Indonesian Pediatric Population with ALL.

PURPOSE: The asparaginase's (ASP) utility for ALL treatment is limited by neutralizing antibodies, which is problematic in countries whose access limited to alternative preparations. ASP antibody levels and activity was measured during remission induction and associated with allergy manifestations. METHODS: E. coli ASP was dosed at 7500 IU/m2. ASP IgG antibody levels were quantified at the beginning and end of induction. ASP activity was measured 24 hours after 1st and 5th dose (standard-risk) or 7th dose (high-risk patients) administration, and within 24 hours in case of allergic reactions. Allergy was monitored by CTCAE version 3. Parametric and non-parametric was performed for data analysis. RESULTS: ASP antibody and activity levels were available in 41/63 consecutive patients. Allergic manifestations occurred in 13/41, with urticaria being the most frequent. There were no significant differences in subject characteristics based on allergic reactions. The 5th dose was the most frequent time of onset. Antibody levels in allergy group at the end of induction did not differ from those at baseline (p<0.05). Using a 24-hour level of 100 mU/mL as a threshold for adequate ASP activity, 6/13 patients with allergy had adequate levels compared to 26/28 patients without (p<0.05). The ASP activity level at the end of induction phase in both groups did not show a significant decrement. CONCLUSION: The E. coli ASP activity with adequate levels were significantly higher in non-allergy group. Its activity level was not accompanied by increment of IgG in allergic group indicates other factors might affect activity levels in allergy group.

Acute Lower Respiratory Infection Profile in Children at Tertiary Hospital Bandung: Is There a Difference Before and During COVID-19 Pandemic?

This study aims to analyze differences of the prevalence and characteristics of acute lower respiratory infection (ALRI) in children at tertiary hospital before and during COVID-19 pandemic. This was an observational analytic study with cross-sectional design involving pediatric patients based on the time of the study which was in 1 year-prepandemic (A) and 1 year-pandemic period (B). For period A inpatient data were retrieved from medical records and period B used pediatric ALRI registry. The ALRI characteristics were analyzed with significance if P < .05. Prevalence in periods A and B were 5.8% (534/9252) and 4.9% (409/8283), respectively. The characteristics of ALRI for clinical, comorbidities, laboratory findings (NLR, TLC), and chest radiograph showed significant differences (P < .05). ALRI as manifestation of confirmed COVID-19 were identified in 16 (4.9%) cases. Prevalence of ALRI in children during COVID-19 pandemic is lower compared to before. There are differences in the characteristics of ALRI in pediatrics.

Serum TNF-α Level as a Possible Predictor of Inhibitor Levels in Severe Hemophilia A.

BACKGROUND: The development of factor VIII (FVIII) inhibitor in patients with hemophilia A (PWHA) is a great challenge for hemophilia care. Both genetic and environmental factors led to complications in PWHA. The development of inhibitory antibodies is usually induced by the immune response. Tumor necrosis factor α (TNF-α), one of the cytokines, might contribute to its polymorphism. In this study, we investigated the clinical factors, level of serum TNF-α, and polymorphism of c.-308G > A TNF - α gene in inhibitor development in severe PWHA. METHODS: A cross-sectional study was conducted among all PWHA in West Java province. The clinical parameters, FVIII, FVIII inhibitor, and serum TNF-α level were assessed. The genotyping of -380G > A TNF-α gene polymorphism was performed using polymerase chain reaction and Sanger sequencing. RESULTS: Among the 258 PWHA, 216 (83.7%) were identified as severe PWHA. The FVIII inhibitor was identified in 90/216 (41.6%) of severe PWHA, consisting of 45 high-titer inhibitors (HTI) and 45 low-titer inhibitors (LTI). There was a significant correlation between serum TNF-α level and the development of HTI (p = 0.043). The cutoff point of serum TNF-α level, which can be used to differentiate between HTI and LTI, was 11.45 pg/mL. The frequency of FVIII replacement therapy was significant only in HTI of severe PWHA regarding serum TNF-α level (p = 0.028). There is no correlation between polymorphisms of -380G > A TNF-α gene and inhibitor development (p = 0.645). CONCLUSIONS: The prevalence of FVIII inhibitor in severe PWHA in West Java, Indonesia, was 41.6%. The frequency of replacement therapy is a risk factor for inhibitor development. Serum TNF-α level might be used to differentiate between high and low inhibitor levels in severe hemophilia A, and this might support decision making regarding treatment options for inhibitor in severe hemophilia A.

Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia.

The administration of high-dose methotrexate (HD-MTX) requires an accurate monitoring of blood MTX levels to determine the regimen of leucovorin rescue and urine alkalinization to prevent toxicity. However, it is technically and logistically challenging to screen patients routinely in limited-resource settings. This study aimed to evaluate blood MTX levels at 24- and 48-hours from start of infusion in relation to clinical toxicity in childhood ALL. METHODS: A prospective cohort study was conducted on 32 consecutive children with acute lymphoblastic leukemia (ALL) who had received at least one cycle of 1 g/m2 HD-MTX intravenous infusion as a part of consolidation treatment based on the 2013 Indonesian ALL Protocol. In total, 68 cycles were evaluated. Serum MTX concentrations were measured using enzyme immunoassay. MTX toxicity was categorized using common toxicity criteria (CTCAE) 3.0 version. The association between MTX level and clinical toxicity was assessed by non-parametric analysis. RESULTS: The 24-hours MTX level was median 29.8 ng/mL (0.065 µmol/L) (IQR 8.1-390.6) with a modest decrease in 48-hours MTX serum level in all cycles (median 28.3 ng/mL and 0.062 µmol/L; IQR 0.35-28.7; p <0.05). The two most common toxicities were hepatotoxicity (32.2%) and neutropenia (30.9%). Nephrotoxicity and febrile neutropenia occurred in 8.8% and 5.8% of patients, respectively, with low percentage of mucositis (4.3%) and thrombocytopenia (5.6%) recorded.  No statistically significant association was found between MTX levels and clinical toxicity, except for liver toxicity. CONCLUSION: Serum MTX levels at 24-hours and 48-hours are low, followed by only 4.4% grade III/IV hepatotoxicity and 26,4% grade III/IV neutropenia. There is no significant association between the clinical toxicity and MTX levels at the two points of measurement. An attempt to increase the MTX dose and/or to introduce a loading dose should be considered in subsequent ALL protocol as supported by further pharmacokinetic MTX studies in the Indonesian population.

Iron Status in Newly Diagnosed ß-Thalassemia Major: High Rate of Iron Status due to Erythropoiesis Drive.

BACKGROUND: Iron overload in severe ß-thalassemia is a serious complication that occurs during the course of the disease. Information about the iron status during initial illness with ß-thalassemia major seemed to be limited. This study is aimed at analyzing iron status, serum hepcidin, and growth differentiation factor 15 (GDF15) levels in newly diagnosed ß-thalassemia major. METHODS: A case-control study was performed at Dr. Hasan Sadikin General Hospital, which included 41 children with newly diagnosed ß-thalassemia major. Age- and sex-matched controls were enrolled. The subjects had no blood transfusion, had normal liver function, and had no sign of inflammation. The groups were compared in terms of the levels of hemoglobin (Hb), serum ferritin (SF), transferrin saturation (TS), serum hepcidin, and GDF15 as iron homeostasis parameters. RESULTS: Of the 41 newly diagnosed ß-thalassemia major patients, those who were less than 24 months old had significantly lower median Hb levels than controls (5.0 vs. 11.7 g/dL, P < 0.001). The median SF and TS levels were significantly higher than those in controls (315.0 vs. 29.0 ng/mL, P < 0.001; 70.6 vs. 16.5%, P < 0.001), and median hepcidin was at the normal limit, but the value was higher in patients (251.0 vs. 123.1 ng/mL, P < 0.001). The median GDF15 level was significantly higher in patients (2,095.3 vs. 342.4 pg/mL, P < 0.001). There was a positive correlation between SF-TS, SF-hepcidin, TS-hepcidin, SF-GDF15, TS-GDF15, and hepcidin-GDF15 (P < 0.001). CONCLUSION: In newly diagnosed ß-thalassemia major, an increase in iron status occurred. This may be caused by increased iron absorption due to massive erythropoietic activity, characterized by an increase in GDF15 levels, which does not cause hepcidin suppression. The iron homeostasis response seems to be physiologically indicated by a tendency to increase hepcidin levels.

Time to Start Delivering Iron Chelation Therapy in Newly Diagnosed Severe ß-Thalassemia.

BACKGROUND: Iron overload is still a major complication of severe ß-thalassemia. Indication to start iron chelation therapy is based on serum ferritin (SF) or transferrin saturation (TS) level or the amount of transfusion. The goal of this study is to analyse the pattern of iron status, the amount of transfusion regarding the time to start iron chelator, and serum hepcidin levels in newly diagnosed severe ß-thalassemia. METHODS: A prospective cohort study was performed at Hasan Sadikin General Hospital on newly diagnosed severe ß-thalassemia patients. Subjects had not received any blood transfusion with normal liver function test, CRP, and IL-6 levels who consumed normal diet according to age. The SF and TS levels indicate iron status, while hepcidin level indicates iron regulator status. Main indicator to start iron chelation therapy when SF level ≥1.000 ng/mL, TS level ≥70%, or after receiving transfusion at least 10 times. Statistical analysis used Mann-Whitney and Spearman. RESULTS: Forty-two newly severe ß-thalassemia, 30 (71.4%), were diagnosed before 1 year old, mean 9.9 ± 6.4 months, range 2-24 months. Range amount of transfusion until SF level reached ≥1,000 ng/mL were 4-12 times, mean 7 ± 2 times. Mean SF and TS level at diagnosis were 365.6 ± 194.9 ng/mL and 67.3 ± 22.5%, while hepcidin level was normal, mean 242.6 ± 58 ng/mL. 36/42 patients have reached SF >1000 ng/mL with amount of transfusion less than 10 times. There was no significant difference of SF, TS, and hepcidin levels when SF >1000 ng/mL in the group with amount of transfusion 7-12 and less than 7 (p = 0.454, p = 0.084, p = 0.765), respectively. A significant positive correlation between SF and amount of transfusion was observed (p < 0.001; r = 0.781). CONCLUSION: Iron overload in severe ß-thalassemia patients might occur earlier even before they received 10 times transfusion. Hepcidin serum level tends to increase when iron overload just started.

Interleukin-18 correlates with interleukin-4 but not interferon-γ production in lymphocyte cultures from atopic dermatitis patients after staphylococcal enterotoxin B stimulation.

BACKGROUND: Staphylococcus aureus (S. aureus) triggers exacerbation of atopic dermatitis (AD) and causes chronic inflammation through the action of various proteins such as staphylococcal enterotoxin B (SEB). SEB has a role in activating interleukin (IL)-18, an important regulator of interferon (IFN)-γ and IL-4, in regards to a therapeutic strategy. OBJECTIVE: To determine the correlation of IL-18 level with the IL-4 and IFN-γ level in lymphocyte cultures from AD patients following SEB stimulation. METHOD: Twenty patients with AD based on the Hanifin and Rajka criteria and 20 healthy subjects as a control group were selected. A 5 ml blood sample from each subject was taken for lymphocyte culture. The culture was stimulated with SEB for two days and the outcomes were assessed by enzyme-linked immunosorbent assays (ELISA) to evaluate the levels of IL-18, IL-4, and IFN-γ. RESULTS: In the AD group, the levels of IL-18, IL-4, and IFN-γ in lymphocyte cultures with SEB were significantly increased compared with non-SEB exposed cells (each p<0.001); similar results were found in the control group. The level of IL-18 was significantly elevated in lymphocyte cultures with SEB stimulation in AD vs. control (p<0.05) and without SEB in AD vs. control (p<0.05). Furthermore, IL-18 levels were significantly correlated with IL-4 levels and score atopic dermatitis (SCORAD) values in AD patients with SEB (r=0.41, p<0.05; and r=0.70, p<0.05, respectively); on the in contrary, there was no correlation between IL-18 and IFN-γ levels (p=0.469). CONCLUSIONS: Our results suggest that IL-18 is correlated with increased of IL-4 levels in SEB-stimulated AD lymphocyte cultures.

Immune response of thalassemia major patients in Indonesia with and without splenectomy.

AIM: to describe non-spesific and specific immune response profile in Indonesian thalassemia major with and without splenectomy. METHODS: this study was held at Thalassaemia Centre, Cipto Mangunkusumo Hospital Jakarta on September 2013-February 2014. A comparative cross sectional study was conducted in healthy, thalassemia major aged more than 12 year and seronegative HIV. They were matched in age and sex for splenectomised and non-splenectomised groups, analysing the non-spesific immune response (neutrophil count and phagocytosis) and specific immune response (count and function of cellular immunity). Infection episodes were also analized as immune response in vivo parameter. RESULTS: splenectomised thalassemia major showed increased neutrophil count but significantly decreased non-spesific immune response (neutrophil phagocytosis). Spesific immune response of splenectomised group presented significantly higher absolute lymphocyte, lymphocyte T, CD4+ and CD8+ counts compared to non-splenectomised thalassemia major (p<0.05). Ratio CD4+/CD8+ were similar in these groups. Serum marker of activated cellular imunity function (IL-2 and TNF-) were similar among two groups. Mild infection episodes on splenectomised and non-splenectomised group were 2.02 (ranged 0 to 12) times and 0.81 (ranged 0 to 8) times (p=0.004), respectively. Severe infection on splenectomised group were sepsis for 2 weeks and diarrhea for 1 week, whereas on non-splenectomised group was typhoid fever for 4 days. CONCLUSION: there were significant differences on immune response among thalassemia major patients. Splenectomised thalassemia major showed a greater degree of susceptibility to infections than non-splenectomised thalassemia major.

Early resuscitation of dengue shock syndrome in children with hyperosmolar sodium-lactate: a randomized single-blind clinical trial of efficacy and safety.

INTRODUCTION: Dengue shock syndrome (DSS) fluid resuscitation by following the World Health Organization (WHO) guideline usually required large volumes of Ringer lactate (RL) that might induce secondary fluid overload. Our objective was to compare the effectiveness of the recommended volume of RL versus a smaller volume of a hypertonic sodium lactate solution (HSL) in children with DSS. The primary end point was to evaluate the effect of HSL on endothelial cell inflammation, assessed by soluble vascular cell adhesion molecule-1 (sVCAM-1) measurements. Secondarily, we considered the effectiveness of HSL in restoring hemodynamic fluid balance, acid-base status, and sodium and chloride balances, as well as in-hospital survival. METHODS: A prospective randomized single-blind clinical trial including 50 DSS children was conducted in the Pediatrics Department of Hasan Sadikin Hospital, Bandung, Indonesia. Only pediatric patients (2 to 14 years old) fulfilling the WHO criteria for DSS and new to resuscitation treatments were eligible. Patients were resuscitated with either HSL (5 ml/kg/BW in 15 minutes followed by 1 ml/kg/BW/h for 12 hours), or RL (20 ml/kg/BW in 15 minutes followed by decreasing doses of 10, 7, 5, and 3 ml/kg BW/h for 12 hours). RESULTS: In total, 50 patients were randomized and included in outcome and adverse-event analysis; 46 patients (8.2 ± 0.5 years; 24.9 ± 1.9 kg; mean ± SEM) completed the protocol and were fully analyzed (24 and 22 subjects in the HSL and RL groups, respectively). Baseline (prebolus) data were similar in both groups. Hemodynamic recovery, plasma expansion, clinical outcome, and survival rate were not significantly different in the two groups, whereas fluid accumulation was one third lower in the HSL than in the RL group. Moreover, HSL was responsible for a partial recovery from endothelial dysfunction, as indicated by the significant decrease in sVCAM-1. CONCLUSION: Similar hemodynamic shock recovery and plasma expansion were achieved in both groups despite much lower fluid intake and fluid accumulation in the HSL group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00966628. Registered 26 August 2009.

Association of complex lipids containing gangliosides with cognitive development of 6-month-old infants.

BACKGROUND: Human breastmilk contains gangliosides which may play an important role in infant neurodevelopment. AIM: A pilot study was conducted to assess the impact of infant formula supplemented with gangliosides from complex milk lipid on cognitive functions of normal healthy infants. STUDY DESIGN: The study was a double-blind, randomized, controlled, parallel group clinical trial in which infants received the treatment or control product from 2 to 8 weeks of age until 24 weeks of age. The control group (n=30) received standard infant formula and the treatment group (n=29) received the same formula supplemented with complex milk lipid to increase the ganglioside content to approximately 11 to 12 µg/ml. A reference group (n=32) consisted of normal healthy exclusively breast-fed infants. OUTCOME MEASURES: Cognitive development using the Griffith Scales and serum gangliosides was measured before (2-8 weeks of age) and after intervention (24 weeks of age). RESULTS: Ganglioside supplementation using complex milk lipids significantly increased ganglioside serum levels (control group vs treatment group, P=0.002) and resulted in increased scores for Hand and Eye coordination IQ (P<0.006), Performance IQ (P<0.001) and General IQ (P=0.041). Cognitive development scores and serum ganglioside levels for the treatment group did not differ from the reference group. CONCLUSIONS: Supplementation of infant formula with complex milk lipid to enhance ganglioside content appears to have beneficial effects on cognitive development in healthy infants aged 0-6 months, which may be related to increased serum ganglioside levels.