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Prolonged cytopenias are a non-specific sign with a wide differential diagnosis. Among inherited disorders, cytopenias predisposing to leukemia require a timely and accurate diagnosis to ensure appropriate medical management, including adequate monitoring and stem cell transplantation prior to the development of leukemia. We aimed to define the types and prevalences of the genetic causes leading to persistent cytopenias in children. The study comprises children with persistent cytopenias, myelodysplastic syndrome, aplastic anemia, or suspected inherited bone marrow failure syndromes, who were referred for genetic evaluation from all pediatric hematology centers in Israel during 2016-2019. For variant detection, we used Sanger sequencing of commonly mutated genes and a custom-made targeted next-generation sequencing panel covering 226 genes known to be mutated in inherited cytopenias; the minority subsequently underwent whole exome sequencing. In total, 189 children with persistent cytopenias underwent a genetic evaluation. Pathogenic and likely pathogenic variants were identified in 59 patients (31.2%), including 47 with leukemia predisposing syndromes. Most of the latter (32, 68.1%) had inherited bone marrow failure syndromes, nine (19.1%) had inherited thrombocytopenia predisposing to leukemia, and three each (6.4%) had predisposition to myelodysplastic syndrome or congenital neutropenia. Twelve patients had cytopenias with no known leukemia predisposition, including nine children with inherited thrombocytopenia and three with congenital neutropenia. In summary, almost one third of 189 children referred with persistent cytopenias had an underlying inherited disorder; 79.7% of whom had a germline predisposition to leukemia. Precise diagnosis of children with cytopenias should direct follow-up and management programs and may positively impact disease outcome.

Impaired neutrophil extracellular trap (NET) formation compromises the host defense after engraftment following hematopoietic stem cell transplantation (HSCT) despite adequate neutrophil counts. The aims of the present study were to determine reference ranges for the activity of key enzymes of NET formation-neutrophil elastase (NE) and myeloperoxidase (MPO)-in a healthy population and to unravel the recovery dynamics of NET formation over time following HSCT, along with NE and MPO enzymatic activities. Reference ranges of NE and MPO activity were derived from 50 healthy volunteers. During 2017 to 2018, 11 consecutive pediatric patients undergoing allogeneic or autologous HSCT were recruited at a single referral center for pediatric hemato-oncology. Patients were followed for up to 1 year following engraftment. The mean reference value was 7.5 ± .4 mU for NE activity and 2.17 ± .4 U for MPO activity in the healthy population, and enzymatic activity of MPO was significantly higher in males. At 3 weeks following neutrophil engraftment, all study participants demonstrated extremely low enzymatic NE activity, whereas MPO activity was above the lower normal reference range at all time points. Reduced NE activity corresponded to the inability to form NETs. Neutrophil function improved over time, but partial impairment persisted for 7 months following transplantation. The ability of neutrophils to form NETs was significantly impaired for 3 weeks after engraftment in the setting of HSCT, exposing patients to bacterial infections. NE activity might serve as a surrogate marker for the capacity of neutrophils to form NETs., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chronic granulomatous disease (CGD) is an innate immunodeficiency with a genetic defect of the nicotinamide adenosine dinucleotide phosphate, reduced, oxidase components. This leads to decreased reactive oxygen species (ROS) production, which renders patients susceptible to life-threatening infections. Over the course of 30 years, we diagnosed CGD in 84 patients from 61 families using functional, molecular, and genetic studies. The incidence of CGD in Israel is 1.05 per 100,000 live-births in the Jewish population and 1.49 in the Israeli Arab population. We diagnosed 52 patients (62%) with autosomal recessive inheritance (AR-CGD) and 32 (38%) with X-linked recessive inheritance (XLR-CGD). Consanguinity was detected in 64% of AR-CGD families (14% in Jews and 50% in Israeli Arabs). We found 36 different mutations (23 in XLR-CGD and 13 in AR-CGD patients), 15 of which were new. The clinical spectrum of CGD varied from mild to severe disease in both XLR and AR forms, although the AR subtype is generally milder. Further, residual ROS production correlated with milder clinical expression, better prognosis and improved overall survival. Patients with recurrent pyogenic infections developed fibrosis and hyperinflammatory states with granuloma formation. The management of CGD has progressed substantially in recent years, evolving from a fatal disease of early childhood to one of long-term survival. Our present cohort displays an encouraging 81% overall long term survival. Early hematopoietic stem cell transplantation is advisable before tissue damage is irreversible. Successful transplantation was performed in 18/21 patients. Therapeutic gene modification could become an alternative cure for CGD. Am. J. Hematol. 92:28-36, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Upon activation, neutrophils release fibers composed of chromatin and neutrophil proteins termed neutrophil extracellular traps (NETs). NETs trap and kill microbes, activate dendritic cells and T cells, and are implicated in autoimmune and vascular diseases. Given the growing interest in the role of neutrophils in cancer immunoediting and the diverse function of NETs, we searched for NETs release by tumor-associated neutrophils (TANs). Using pediatric Ewing sarcoma (ES) as a model, we retrospectively examined histopathological material from diagnostic biopsies of eight patients (mean ± SD age of 11.5 ± 4.7 years). TANs were found in six patients and in two of those we identified NETs. These two patients presented with metastatic disease and despite entering complete remission after intensive chemotherapy had an early relapse. NETs were not identified in the diagnostic biopsies of two patients with localized disease and two with metastatic disease. This study is the first to show that TANs in ES are activated to make NETs, pointing to a possible role of NETs in cancer.

Purpose: Intense exercise bouts are associated with a reduction of immune function and increased susceptibility to infections. Neutrophils act as a first line of defense to eliminate infectious agents and are also involved in muscle tissue inflammatory response to exercise. Intensive exercise suppresses several neutrophil functions including chemotaxis. The study investigates the pathophysiological mechanisms of impaired chemotaxis after submaximal aerobic exercise., Methods: Twenty-three healthy physically active adult males were tested before and 24 h after 30 min of treadmill running at 75% VO2max. N-formyl-Met-Leu-Phe (fMLP)-stimulated neutrophil migration, polarization, adherence, expression of adhesion molecules (CD11b/CD18), and chemotactic receptor (C5aR) were assessed preexercise and postexercise., Results: Neutrophil chemotaxis and polarization were found to be impaired 24 h postexercise. Adherence was impaired 24 h postexercise as well, but the expression of the adhesion molecule CD11b/CD18 was not affected. Further, the availability of the C5aR was found to be unaffected 24 h postaerobic exercise., Conclusions: The pathophysiological mechanism of the impaired chemotaxis is likely related to the impaired postexercise neutrophil adherence and polarization but not to changes in the chemotactic receptor availability.

Transfusion-related acute lung injury (TRALI) is associated with administration of all plasma containing blood products. We present a 14-year-old adolescent diagnosed with idiopathic thrombocytopenic purpura who developed acute respiratory insufficiency compatible with TRALI within 5 hr following intravenous anti-D. Full blown noncardiogenic pulmonary edema was noted after 9 hr. Mechanical ventilation was not required and the patient made a full recovery after 36 hr. Analysis of the anti-D preparation revealed reactivity against the neutrophil FcgammaRIIIb. A postinfusion serum sample contained antibodies against class I human HLA-A11 antigen. Clinicians should consider TRALI in patients developing unexplained dyspnea after receiving intravenous anti-D., (Copyright 2008 Wiley-Liss, Inc.)

Background: The rate of breast-feeding in Israel has increased over the last two decades but is still lower than rates in other developed countries that have taken an active role in promoting breast-feeding., Objective: To determine breast-feeding patterns and the association between sociodemographic characteristics and breast-feeding in the Tel Aviv district., Methods: The mothers of infants aged 2, 4, 6 and 12 months, attending 59 well-baby clinics in the Tel Aviv district, were interviewed by telephone. Singleton infants who weighed less than 2,000 g and multiple-gestation infants were excluded from the study. The questions covered background data, sociodemographic characteristics of the family, and breast-feeding practices. Stepwise logistic regression was used to analyze the association between breast-feeding and various sociodemographic characteristics., Results: Altogether, 78.5% of the mothers (1,307/1,665) initiated breast-feeding. The rate of breast-feeding at 2, 4, 6 and 12 months was 55.8, 36.8, 29.9 and 11.8%, respectively. Only 35.8% of the infants at 2 months and 11.2% at 6 months were exclusively breast-fed. The mean duration of breast-feeding was 5.2 +/- 0.2 months. Grand multiparas (> or = 5 children) had a significantly higher rate of breast-feeding than women with one to four children (P < 0.001). More likely to breast-feed for 2 weeks or longer were women married to Yeshiva students (odds ratio = 5.3), women with > or = 13 years education (OR = 2.1), and women on maternity leave (OR = 1.6). The predictors for breast-feeding for 6 months or longer were similar., Conclusions: Although the rate of breast-feeding initiation in central Israel was 78.5%, only 29.9% of the mothers continue to breast-feed for 6 months. Already at a young age, an appreciable number of breast-fed infants receive infant formula. Breast-feeding promotion should focus on less educated women, homemakers, and families with one to four children.