Serum interleukin-33 and soluble suppression of tumorigenicity 2 in pediatric leukemia with febrile neutropenia.

The purpose of this study was to evaluate the association between interleukin-33 (IL-33) and its receptor Soluble Suppression of Tumorigenicity-2 (sST2) levels and bacterial infections during febrile neutropenia (FN) in pediatric patients with acute lymphoblastic leukemia (ALL). In this prospective, case-control study, participants were divided into 3 groups: ALL patients with FN (Group A), ALL patients without neutropenia and fever (Group B), and healthy children without infection and chronic disease (Group C). There were 30 cases in each group. Blood samples for IL-33 and sST2 have been drawn from patients in Group A before the initiation of treatment and on days 1 and 5 of treatment, and from patients in Groups B and C at initiation. At admission, mean IL-33 level (39.02 ± 26.40 ng/L) in Group B and mean sST2 level (185.3 ± 371.49 ng/ml) in Group A were significantly higher than the other groups (p = 0.038, p < 0.001, respectively). No difference was observed in the mean IL-33 and sST2 levels in the 5-day follow-up of patients in Group A (p = 0.82, p = 0.86, respectively). IL-33 and sST2 levels were not associated with fever duration, neutropenia duration or length of hospitalization. While C-reactive protein (CRP) was significantly higher in patients with positive blood culture (p = 0.021), IL-33 (p = 0.49) and sST2 (p = 0.21) levels were not associated with culture positivity.  Conclusion: IL-33 and sST2 levels were not found valuable as diagnostic and prognostic markers to predict bacterial sepsis in patients with FN. What is Known: • Neutropenic patients are at high risk of serious bacterial and viral infections, but the admission symptom is often only fever. • Febrile neutropenia has a high mortality rate if not treated effectively. What is New: • Febrile neutropenia is not only caused by bacterial infections. Therefore, new biomarkers should be identified to prevent overuse of antibiotics. • Specific biomarkers are needed to diagnose bacterial sepsis in the early phase of febrile neutropenia.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Evaluation of coagulation parameters and impact of transfusion on coagulation in patients with beta thalassemia major.

There have been several studies that have shown that patients with beta thalassemia major are at a higher risk of thrombosis due to the procoagulant activity of thalassemic erythrocytes, decreased liver synthetic function, increased platelet activity and vascular endothelial activation attributed to chronic oxidative stress, although there are no established tests to predict thrombotic risk in TM patients. In this study, we evaluated whether or not the platelet function analyser (PFA-200) and thrombin generation test (TGT) would be useful tools to identify hypercoagulability and risk of thrombosis in thalassemia major patients. The study included 50 patients with thalassemia major and 104 healthy control group. Pretransfusion and posttransfusion PFA-200 and TGT results were compared with control group. We found that median C/ADP and C/EPI values in the thalassemia major group were greater in both the pre and posttransfusion samples than the C/ADP and C/EPI results from the control group. The TGT results showed there was no difference between control group and the results from the thalassemia major group. The TGT and PFA-200 testing did not identify hypercoagulability nor identify clear testing parameters to predict a thalassemia major patient's risk of thrombosis. There may be other mechanisms/causes yet unidentified that could better explain thalassemia major patient's increased risk from thromboembolic events.

Analysis of fresh frozen plasma utilization indications in children: An audit of a tertiary care hospital in Turkey.

BACKGROUND: Although indications of fresh frozen plasma (FFP) usage are limited to certain circumstances in children, there is an increasing trend towards inappropriate usage are reported in clinical practice. The aim of this study was to evaluate the appropriateness of pediatric FFP utilization in our tertiary care hospital. METHODS: This prospective observational study was conducted at a tertiary care academic pediatric hospital. All FFP orders were evaluated for appropriateness over a 4-monts period by 2 hematologists. Data collected include demographic information, diagnosis, FFP transfusion indication, pre-transfusion coagulation tests, surgical procedure or bleeding status, and transfusion reactions. RESULTS: Three hundred twenty-four patients (57 % males, 43 % females) were transfused in 987 episodes. The mean age of the patients was 5.4±5.7 years. The majority of the patients (33 %) were under 1 y of age and the products were primarily utilized by pediatric and cardiovascular intensive care units. Pre-transfusion coagulation testing was only available in 674 (68 %) of the transfusion episodes. The rate of appropriate FFP transfusion episodes was 59 % (587/987). Inappropriate usage was mostly related to sepsis and minor coagulation abnormalities without bleeding. The higher rates of inappropriate transfusion orders were observed in pediatric and neonatal intensive care units, and hematology/oncology departments. CONCLUSIONS: Inappropriate use of FFP in children remains a significant challenge. The regular audit and sustainable education programs targeting the efficient use of FFP for health professionals at the national level can improve transfusion practices.

HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia.

The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis.

Hepatitis-Associated Aplastic Anemia: Etiology, Clinical Characteristics and Outcome.

Hepatitis-associated aplastic anemia (HAA) is a form of acquired aplastic anemia (AA) in which bone marrow failure develops after an acute attack of hepatitis. Bone marrow failure leading to AA is generally severe in cases of HAA and fatal if left untreated. This retrospective multicenter study investigated clinical and laboratory characteristics, possible causes, treatment, and outcome of HAA in children. Twenty patients from 8 centers were included in the study. Aspartate aminotransferase and alanine aminotransferase were <3 to 5×upper limit of normal (ULN) in 2 patients, <5 to 10×ULN in 2 patients, and >10×ULN in 16 patients. Acute liver failure developed in 5 (29%) patients. Pancytopenia was simultaneously present in 6 of 20 (30%) patients. Eleven of the 20 patients (55%) were alive, in remission and transfusion free. Those who were alive either had undergone hematopoietic stem cell transplantation and/or immunosuppressive treatment, except 1 patient who had received no treatment. Patients with the diagnosis of acute hepatitis should be evaluated and followed up carefully for presence of cytopenia, so that definitive treatment of AA can be initiated in a timely and appropriate manner when needed.

An outbreak of Ralstonia pickettii bloodstream infection among pediatric leukemia patients.

BACKGROUND: Ralstonia pickettii is an opportunistic waterborne microbe which can survive in many kinds of solutions. Contamination of these solutions may result as outbreaks, which can be mortal for immuncompromised patients. Herein we report an outbreak of R. pickettii related to contaminated saline infusion in our center. METHODS: This study was conducted in Ankara Pediatric City Hospital. An outbreak occured in Pediatric Hematology and Oncology Unit between August 28, 2019 and September 13, 2019. When the outbreak occured, infection control team began an investigation. Environmental samples were collected in order to find the source of the outbreak. RESULTS: A total of 11 patients with catheter related blood stream infection caused by R. pickettii who were diagnosed with leukemia were affected. None of the patients infected with R. pickettii died during the outbreak. A total of seventy environmental samples were cultured with the purpose of finding the source of outbreak. R. pickettii grew in normal saline solution culture and all isolates had the same clone of R. pickettii. The outbreak lasted two weeks and was controlled by stopping the usage and sending back the saline solutions belonging to the same manufacturing batch. CONCLUSIONS: We reported an outbreak of R. pickettii BSIs in highly immunocompromised patients due to contaminated intravascular solution, which was rapidly controlled by infection control measures. Vigilant surveillance by hospital infection control teams and prompt investigation to identify the source of nosocomial infections are crucial to stop an outbreak.

Evaluation of early-onset cardiotoxic effects of anthracyclines used during the treatment of childhood acute lymphoblastic leukemia by speckle-tracking echocardiography.

OBJECTIVE: Anthracyclines are widely used in the treatment of acute lymphoblastic leukemia (ALL). However, cardiotoxicity is the most critical side effect that requires dose limitation. It is thought to occur at first exposure, but the clinical presentation may occur years later. In this study, we aimed to determine the time of initial damage and cardiotoxicity that develops in children with ALL. METHODS: In this prospective study, 13 patients with newly diagnosed intermediate-risk precursor B cell ALL treated with the ALL-IC BFM 2009 protocol were included. Conventional echocardiography, tissue Doppler imaging (TDI), and speckle-tracking echocardiography (STE) were performed in all the patients before chemotherapy, after completing the induction phase, and at the end of the reinduction phase. RESULTS: The mean age of the patients was 7.8±4.6 (3.1-16.3) years. Myocardial velocity during systole (Sm) determined by TDI at the interventricular septum significantly decreased during the induction phase. Despite a decrease in STE parameters, a statistically significant reduction was determined in the global longitudinal strain rate at both left and right ventricles at the end of the induction. Nevertheless, a statistically significant increase was observed among the conventional echocardiographic findings in the left ventricular end-diastolic diameter at the end of the reinduction. CONCLUSION: During the treatment of ALL, subclinical anthracycline-associated cardiotoxicity develops in the early stages of treatment. The findings detected by TDI and STE could be missed by conventional echocardiography. We recommend evaluating patients with these newly developed techniques to detect subclinical cardiotoxicity at an early stage and starting appropriate therapy on time.

Pneumatosis cystoides intestinalis: A rare complication after hematopoietic stem cell transplantation.

BACKGROUND: Pneumatosis cystoides intestinalis (PCI) is a disorder in which widespread air sacs are present in mucosa, submucosa, subserosa, and intraabdominal area of the intestinal wall. It has a heterogeneous clinical presentation as a rare complication of intestinal graft-versus-host disease (GVHD). Computed tomography is the preferred imaging method for the diagnosis. Since the air sacs could be ruptured spontaneously, the presence of free air in the peritoneal cavity does not confirm intestinal perforation. The conservative treatment approach is sufficient in cases that do not require urgent surgical intervention, such as perforation or obstruction. CASE: Here, we present a 2.5-year-old patient diagnosed with primary hemophagocytic lymphohistiocytosis (pHLH), who underwent allogeneic hematopoietic stem cell transplantation from a matched unrelated donor (MUD) and developed PCI secondary to intestinal GVHD 14th months after HSCT. CONCLUSIONS: Pneumatosis cystoides intestinalis, which is a rare complication, should be kept in mind, especially in patients with intestinal GVHD and receiving intensive immunosuppressive, octreotide, and steroid treatment after HSCT.

Thrombin generation in children with febrile neutropenia.

BACKGROUND: Febrile neutropenia (FN) is a common and serious complication in patients with leukemia. Hemostasis and inflammation are two interrelated systems in response to infection. We aimed to investigate the course of thrombin formation in febrile neutropenia attack of children with acute lymphoblastic leukemia (ALL). METHODS: Thrombin generation was monitored in children treated for ALL at diagnosis of febrile neutropenia (FN) (t < sub > 0 < /sub > ), at 48 < sup > th < /sup > hour of FN (t1) and after recovery from neutropenia (t < sub > 2 < /sub > ). RESULTS: Twenty-nine patients and 50 healthy children as control were enrolled into the study. Mean endogenous thrombin potential (ETP) and mean peak value of thrombin results at t < sub > 1 < /sub > were significantly higher than at t < sub > 0 < /sub > , t < sub > 2 < /sub > and control groups, respectively. A positive but statistically nonsignificant correlation between ETP values at t < sub > 1 < /sub > and duration of neutropenia was observed. CONCLUSION: Although thrombin generation is enhanced both due to chemotherapy or malignancy itself, our results revealed that thrombin formation also increased in neutropenic infection of children with leukemia.

Health-related Quality of Life for Children With Leukemia: Child and Parental Perceptions.

BACKGROUND: The importance of health-related quality of life (HRQoL) in patients with acute lymphoblastic leukemia (ALL) has increased in recent years. This study aimed to assess HRQoL in children with ALL, affecting factors, and the relationship between parent proxy-report and child self-report HRQoL. MATERIALS AND METHODS: A total of 59 children and their parents (both mother and father) were enrolled in this cross-sectional study. Turkish version of the Pediatric Quality of Life Inventory (PedsQL) 3.0 Cancer Modules were used to determine HRQoL. RESULTS: According to subscales of the self-report form, nausea and operational anxiety scores differed significantly by the treatment status; communication score varied considerably by the hospitalization length of stay; pain and hurt, cognitive problems, and perceived physical appearance scores differed significantly by the maternal chronic disease status (P<0.05). The presence of maternal chronic disease was significantly related to the total score of the parent-proxy report (mother) (P<0.05). There was a moderate correlation between total scores of child and mother (P<0.05, r=0.419) but not with the father. CONCLUSION: Children on-treatment had significant problems in nausea and procedural anxiety subscales; however, children who were hospitalized more had fewer issues in the communication subscale. Also, children whose mother had chronic disease had poorer HRQoL regarding pain and hurt cognitive problems and treatment anxiety. Given the importance of assessment and monitoring HRQoL in children with ALL, health professionals should be aware of how parents' chronic disease affects HRQoL. Psychosocial support should be provided to children and their parents, especially for those whose parents have a chronic illness.

Children With Behçet Disease-associated Thrombosis: A Single-Center Experience.

Behçet disease (BD) is a systemic vasculitis that can be complicated with thrombosis, which is an important cause of mortality and morbidity. The course of BD is more severe, and the diagnosis is usually delayed. In children, thrombosis associated with BD is very rare. In this study, we aimed to evaluate the characteristics of children with BD complicated with thrombosis. Forty-six patients with BD who were followed-up at a pediatric rheumatology department between January 2012 and September 2019 were evaluated retrospectively. Thrombosis was detected in 10 patients (21.7%), and it was the first sign of BD in 7 patients. Four patients had cerebral sinus venous thrombosis, 4 patients had deep-vein thrombosis, 1 patient had renal vein thrombosis, 1 had pulmonary artery thrombosis, and 1 had intracardiac thrombosis. None of the patients had arterial thrombosis. All patients had received anticoagulant therapy with immunosuppressive treatment. Any complication due to anticoagulant therapy was not detected. One patient had recurrent thrombosis, and none of the patients died during follow-up. Vasculitic diseases such as BD may cause a predisposition to thrombosis, and thrombosis might be the first sign of BD. Therefore, in children presenting with unprovoked thrombosis, BD should also be investigated.

Efficacy and safety of granulocyte transfusion in children: A single-center experience.

BACKGROUND: Granulocyte suspension transfusion (GTx) can be used in severely neutropenic patients with infections that cannot be controlled despite appropriate antibiotic therapy. OBJECTIVE: We aimed to evaluate the effectiveness and safety of GTx for the treatment of febrile neutropenia (FEN) in the pediatric age group. METHODS: Patients who underwent GTx in the Hematology Clinic of Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital between 2013 and 2017 were evaluated retrospectively. Hematologic and clinical response rates, effects on survival, and adverse effects were investigated. Clinical response was defined at two time points: clinical response I was evaluated after each transfusion, while clinical response II was evaluated after the final GTx in a FEN episode. RESULTS: During the study period, 343 GTx were given 107 FEN episodes of 74 patients. The mean number of granulocyte suspensions administered per patient and per FEN episode was 4.6 units and 3.2 units. The mean GTx volume administered was 237 ± 40 mL, and the mean granulocyte count was 2.8 ± 1.3 x 1010 /unit. Hematologic response was attained in 163 (47.6%) of 343 transfusions. Clinical response I was obtained in 88 (25.7%) of the GTx, and clinical response II was attained in 83 (78.5%) of 107 episodes. Life-threatening adverse event was not observed. The cumulative 1-month and 3-month survival rates were 87.8% and 76.5%, respectively. CONCLUSION: High hematologic response and clinical recovery rates were achieved with GTx, with no limiting adverse effects. Granulocyte transfusion appears to be a safe and effective treatment in pediatric patients with FEN.

Autoimmune atrophic gastritis: The role of Helicobacter pylori infection in children.

BACKGROUND: Autoimmune atrophic gastritis (AIG) is very rare in children. Despite a better understanding of histopathologic changes and serological markers in this disease, underlying etiopathogenic mechanisms and the effect of Helicobacter pylori (H pylori) infection are not well known. We aimed to investigate the relation between AIG and H pylori infection in children. MATERIALS AND METHODS: We evaluated the presence of AIG and H pylori infection in fifty-three patients with positive antiparietal cell antibody (APCA). Demographic data, clinical symptoms, laboratory and endoscopic findings, histopathology, and presence of H pylori were recorded. RESULTS: The children were aged between 5 and 18 years, and 28 (52.8%) of them were male. Mean age was 14.7 ± 2.6 years (median: 15.3; min-max: 5.2-18), and 10 (18.8%) of them had AIG confirmed by histopathology. In the AIG group, the duration of vitamin B12 deficiency was longer (P = .022), hemoglobin levels were lower (P = .018), and APCA (P = .039) and gastrin (P = .002) levels were higher than those in the non-AIG group. Endoscopic findings were similar between the two groups. Intestinal metaplasia was higher (P = .018) in the AIG group. None of the patients in the AIG group had H pylori infection (P = .004). One patient in the AIG group had enterochromaffin-like cell hyperplasia. CONCLUSIONS: Our results show that, in children, H pylori infection may not play a role in AIG. AIG could be associated with vitamin B12 deficiency, iron deficiency, and APCA positivity in children. APCA and gastrin levels should be investigated for the early diagnosis of AIG and intestinal metaplasia.