Central Line-Associated Bloodstream Infection Due to Elizabethkingia anophelis: Case Report and Literature Review on Pediatric Infections.

Elizabethkingia anophelis is an opportunistic pathogen causing lifethreatening infections in humans, particularly in immunocompromised patients, neonates and the elderly. We report a case of central line-associated bloodstream infection by E. anophelis in a 2.5-year-old girl with acute lymphoblastic leukemia successfully treated with a combination of piperacillin/tazobactam and amikacin. The literature was also reviewed on pediatric infections caused by E. anophelis, focusing on clinical manifestations, underlying medical conditions, treatment and outcome. Accurate identification with MALDI-TOF, or using molecular techniques, is of the utmost importance because treatment and prognosis differ depending on the species. Considering that E. anophelis is multiresistant to antibiotics and that inappropriate antimicrobial therapy is an independent risk factor for mortality, the early, accurate identification of bacterial species and prompt effective treatment are essential to achieve optimal therapeutic outcomes.

B-NHL Cases in a Tertiary Pediatric Hematology-Oncology Department: A 20-Year Retrospective Cohort Study.

Non-Hodgkin lymphoma (NHL) is among the five most common pediatric cancer diagnoses in children and adolescents and consists of a heterogeneous group of lymphoid tissue malignancies -with B-cell-derived NHL accounting for nearly 80% of cases. Novel and high-throughput diagnostic tools have significantly increased our understanding of B-NHL biology and molecular pathogenesis, leading to new NHL classifications and treatment options. This retrospective cohort study investigated 17 cases of both mature B-cell NHL (Burkitt lymphoma or BL; Diffuse large B-cell lymphoma or DLBCL; Primary mediastinal large B-cell lymphoma or PMBCL; Follicular lymphoma or FL) and immature B-cell progenitor NHL (B-lymphoblastic lymphoma or BLL) that were treated in a tertiary Pediatric Hematology-Oncology Department during the last 20 years. Modern NHL protocols for children, adolescents, and young adults, along with the addition of rituximab, are safe and efficient (100% overall survival; one relapse). Elevated ESR was more prevalent than elevated LDH. Analyses have focused on immune reconstitution (grade ≥3 infections, lymphocyte and immunoglobulin levels recovery) and body-mass-index changes post-treatment, late effects (in 53% of patients), and the presence of histology markers BCL2, BCL6, CD30, cMYC, and Ki-67%. One patient was diagnosed with a second malignant neoplasm (papillary thyroid cancer).

The Diverse Genomic Landscape of Diamond-Blackfan Anemia: Two Novel Variants and a Mini-Review.

Diamond-Blackfan anemia (DBA) is a ribosomopathy characterized by bone marrow erythroid hypoplasia, which typically presents with severe anemia within the first months of life. DBA is typically attributed to a heterozygous mutation in a ribosomal protein (RP) gene along with a defect in the ribosomal RNA (rRNA) maturation or levels. Besides classic DBA, DBA-like disease has been described with variations in 16 genes (primarily in GATA1, followed by ADA2 alias CECR1, HEATR3, and TSR2). To date, more than a thousand variants have been reported in RP genes. Splice variants represent 6% of identifiable genetic defects in DBA, while their prevalence is 14.3% when focusing on pathogenic and likely pathogenic (P/LP) variants, thus highlighting the impact of such alterations in RP translation and, subsequently, in ribosome levels. We hereby present two cases with novel pathogenic splice variants in RPS17 and RPS26. Associations of DBA-related variants with specific phenotypic features and malignancies and the molecular consequences of pathogenic variations for each DBA-related gene are discussed. The determinants of the spontaneous remission, cancer development, variable expression of the same variants between families, and selectivity of RP defects towards the erythroid lineage remain to be elucidated.

Infectious Complications of Targeted Therapies in Children with Leukemias and Lymphomas.

The aim of this review is to highlight mechanisms of immunosuppression for each agent, along with pooled analyses of infectious complications from the available medical literature. Rituximab confers no increase in grade ≥3 infectious risks, except in the case of patients with advanced-stage non-Hodgkin lymphoma. Gemtuzumab ozogamicin links with high rates of grade ≥3 infections which, however, are comparable with historical cohorts. Pembrolizumab exhibits a favorable safety profile in terms of severe infections. Despite high rates of hypogammaglobulinemia (HGG) with blinatumomab, low-grade ≥3 infection rates were observed, especially in the post-reinduction therapy of relapsed B-acute lymphoblastic leukemia. Imatinib and nilotinib are generally devoid of severe infectious complications, but dasatinib may slightly increase the risk of opportunistic infections. Data on crizotinib and pan-Trk inhibitors entrectinib and larotrectinib are limited. CAR T-cell therapy with tisagenlecleucel is associated with grade ≥3 infections in children and is linked with HGG and the emergence of immune-related adverse events. Off-label therapies inotuzumab ozogamicin, brentuximab vedotin, and venetoclax demonstrate low rates of treatment-related grade ≥3 infections, while the addition of bortezomib to standard chemotherapy in T-cell malignancies seems to decrease the infection risk during induction. Prophylaxis, immune reconstitution, and vaccinations for each targeted agent are discussed, along with comparisons to adult studies.

MicroRNAs and the Diagnosis of Childhood Acute Lymphoblastic Leukemia: Systematic Review, Meta-Analysis and Re-Analysis with Novel Small RNA-Seq Tools.

MicroRNAs (miRNAs) have been implicated in childhood acute lymphoblastic leukemia (ALL) pathogenesis. We performed a systematic review and meta-analysis of miRNA single-nucleotide polymorphisms (SNPs) in childhood ALL compared with healthy children, which revealed (i) that the CC genotype of rs4938723 in pri-miR-34b/c and the TT genotype of rs543412 in miR-100 confer protection against ALL occurrence in children; (ii) no significant association between rs2910164 genotypes in miR-146a and childhood ALL; and (iii) SNPs in DROSHA, miR-449b, miR-938, miR-3117 and miR-3689d-2 genes seem to be associated with susceptibility to B-ALL in childhood. A review of published literature on differential expression of miRNAs in children with ALL compared with controls revealed a significant upregulation of the miR-128 family, miR-130b, miR-155, miR-181 family, miR-210, miR-222, miR-363 and miR-708, along with significant downregulation of miR-143 and miR-148a, seem to have a definite role in childhood ALL development. MicroRNA signatures among childhood ALL subtypes, along with differential miRNA expression patterns between B-ALL and T-ALL cases, were scrutinized. With respect to T-ALL pediatric cases, we reanalyzed RNA-seq datasets with a robust and sensitive pipeline and confirmed the significant differential expression of hsa-miR-16-5p, hsa-miR-19b-3p, hsa-miR-92a-2-5p, hsa-miR-128-3p (ranked first), hsa-miR-130b-3p and -5p, hsa-miR-181a-5p, -2-3p and -3p, hsa-miR-181b-5p and -3p, hsa-miR-145-5p and hsa-miR-574-3p, as described in the literature, along with novel identified miRNAs.

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies.

Since 1985 when the first agent targeting antigens on the surface of lymphocytes was approved (muromonab-CD3), a multitude of such therapies have been used in children with hematologic malignancies. A detailed literature review until January 2021 was conducted regarding pediatric patient populations treated with agents that target CD2 (alefacept), CD3 (bispecific T-cell engager [BiTE] blinatumomab), CD19 (denintuzumab mafodotin, B43, BiTEs blinatumomab and DT2219ARL, the immunotoxin combotox, and chimeric antigen receptor [CAR] T-cell therapies tisagenlecleucel and axicabtagene ciloleucel), CD20 (rituximab and biosimilars, 90Y-ibritumomab tiuxetan, ofatumumab, and obinutuzumab), CD22 (epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, BiTE DT2219ARL, and the immunotoxin combotox), CD25 (basiliximab and inolimomab), CD30 (brentuximab vedotin and iratumumab), CD33 (gemtuzumab ozogamicin), CD38 (daratumumab and isatuximab), CD52 (alemtuzumab), CD66b (90Y-labelled BW 250/183), CD248 (ontuxizumab) and immune checkpoint inhibitors against CTLA-4 (CD152; abatacept, ipilimumab and tremelimumab) or with PD-1/PD-L1 blockade (CD279/CD274; atezolizumab, avelumab, camrelizumab, durvalumab, nivolumab and pembrolizumab). The aim of this narrative review is to describe treatment-related invasive fungal diseases (IFDs) of each category of agents. IFDs are very common in patients under blinatumomab, inotuzumab ozogamicin, basiliximab, gemtuzumab ozogamicin, alemtuzumab, and tisagenlecleucel and uncommon in patients treated with moxetumomab pasudotox, brentuximab vedotin, abatacept, ipilimumab, pembrolizumab and avelumab. Although this new era of precision medicine shows promising outcomes of targeted therapies in children with leukemia or lymphoma, the results of this review stress the necessity for ongoing surveillance and suggest the need for antifungal prophylaxis in cases where IFDs are very common complications.

Acinetobacter baumannii Antibiotic Resistance Mechanisms.

Acinetobacter baumannii is a Gram-negative ESKAPE microorganism that poses a threat to public health by causing severe and invasive (mostly nosocomial) infections linked with high mortality rates. During the last years, this pathogen displayed multidrug resistance (MDR), mainly due to extensive antibiotic abuse and poor stewardship. MDR isolates are associated with medical history of long hospitalization stays, presence of catheters, and mechanical ventilation, while immunocompromised and severely ill hosts predispose to invasive infections. Next-generation sequencing techniques have revolutionized diagnosis of severe A. baumannii infections, contributing to timely diagnosis and personalized therapeutic regimens according to the identification of the respective resistance genes. The aim of this review is to describe in detail all current knowledge on the genetic background of A. baumannii resistance mechanisms in humans as regards beta-lactams (penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors), aminoglycosides, tetracyclines, fluoroquinolones, macrolides, lincosamides, streptogramin antibiotics, polymyxins, and others (amphenicols, oxazolidinones, rifamycins, fosfomycin, diaminopyrimidines, sulfonamides, glycopeptide, and lipopeptide antibiotics). Mechanisms of antimicrobial resistance refer mainly to regulation of antibiotic transportation through bacterial membranes, alteration of the antibiotic target site, and enzymatic modifications resulting in antibiotic neutralization. Virulence factors that may affect antibiotic susceptibility profiles and confer drug resistance are also being discussed. Reports from cases of A. baumannii coinfection with SARS-CoV-2 during the COVID-19 pandemic in terms of resistance profiles and MDR genes have been investigated.

Play and medical play in teaching pre-school children to cope with medical procedures involving needles: A systematic review.

AIM: Most toddlers experience pain and distress during doctor or dental visits. Aim of this systematic review was to investigate the role of play-based interventions in pain and fear or distress management in pre-school children (aged from 2 to 6 years old) undergoing needle-related medical procedures adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (registration number: CRD42020192161). METHODS: The key database that was searched was PubMed/MEDLINE along with references of relevant review studies. Only randomised controlled trials (RCTs) that fulfilled inclusion and eligibility criteria were selected for analysis. Methodological quality was evaluated using the Cochrane Collaboration's Risk of Bias Tool for RCTs and Review Manager version 5.4 was utilised in order to calculate standardised mean differences (SMDs) and create a forest plot for included studies that presented data on self-reported pain ratings. Primary outcomes refer to pain, anxiety and fear assessments, while secondary outcomes refer to physiological measures and cortisol levels. RESULTS: All included RCTs suffered from high risk of bias that relied on selection and blinding methodology, while other sources of bias were also present in some cases. Despite low-quality of evidence, play-based interventions seem to favour less self-reported pain (SMD -0.39; 95% CI: -0.67 to -0.12; I2 = 84%). CONCLUSION: Limitations of evidence, except from high risk of bias, include inconsistency in reporting primary outcome assessments and study designs that preclude reproducibility. Play-based techniques seem to contribute to pre-schoolers' coping towards needle-related medical procedures and further research is warranted in order to explore clinical benefits.

Data regarding 2D:4D and other digit ratios in Greek population.

Second-to-fourth digit ratio (2D:4D) is a sexually dimorphic biometric marker, which is influenced by prenatal estrogen levels and reflects to the hormonal profile of each individual. Exposure to environmental estrogens was common in the past. Their endocrine-disrupting action, combined with their long half-time, may have a feminizing effect and an impact on health. A stratified sample of 160 Greek people was selected by random procedures and fingers' length was measured by means of an electronic caliper. Based on preliminary statistical analysis, middle aged persons, corresponding to birth in the period 1947-1972, were found to differ significantly from the rest and the original sample was subsequently divided into three age subgroups (≤37, 38-63 and ≥64 years old). 2D:4D ratio was found significantly higher in Greek people aged from 38 to 63 years old, although sexual dimorphism remained unaffected. The other digit ratios followed the same pattern, with people aged less than 38 years to share equivalent ratios with people aged more than 63 years.

Candidemia complicating biliary atresia in an infant with hemoglobinopathy.

Both biliary atresia and hemoglobinopathies have been associated with a higher incidence of bloodstream infections. We hereby present the case of a female infant of Nigerian descent with extrahepatic biliary atresia and double heterozygocity for sickle cell disease and alpha-thalassemia. Kasai hepatoportoenterostomy was performed in the child's sixth week of life. Bloodstream infections occurred two months post-hepatoportoenterostomy, even though the infant was still in prophylactic antibiotic treatment: the first was due to Candida albicans and was followed by bacteremia due to Escherichia coli. A third infection, confined to the skin only, was due to Acinetobacter spp. Treatment options, predisposing factors, and the pathophysiology of bloodstream infections in patients with biliary atresia and aberrant hemoglobin are discussed herein.

Hem biliyer atrezi, hem de hemoglobinopatilerde, kan dolasimi enfeksiyonu sikligi daha fazladir. Burada, ekstrahepatik biliyer atrezisi ve "sickle-cell" hastaligi ve alfa-talasemi için çift heterozigot olan Nijerya kökenli bir kiz bebegi sunuyoruz. Çocuga yasaminin altinci haftasinda Kasai hepatoportoenterostomi uygulandi. Halen profilaktik antibiyotik tedavisi almakta olmasina ragmen, hepatoportoenterostomiden iki ay sonra kan dolasimi enfeksiyonlari ortaya çikmistir: birincisi kandida albikansa bagli iken, bunu Escherichia coli'e bagli bakteriyemi izlemistir. Sadece cilt ile sinirli kalan üçüncü bir enfeksiyon Acinetobacter spp'e bagli olarak gelismistir. Bu yazida biliyer atrezi ve anormal hemoglobini olan hastalarda, tedavi seçenekleri, predispozan faktörler ve kan dolasimi enfeksiyonlarinin patofizyolojisi tartisilmistir.

Invasive fungal infections in paediatric patients treated with macromolecular immunomodulators other than tumour necrosis alpha inhibitors.

An expanding list of immunomodulatory or immunosuppressive monoclonal antibodies (mAbs) and biologic therapeutics is currently entering clinical practice, particularly in the areas of oncology, transplantation and autoimmune disorders. These agents are directed against molecules or cells involved in inflammation and immunity and may therefore be associated with serious and opportunistic infections. The purpose of this review was to critically analyse the literature on invasive fungal infections (IFIs) occurring in association with mAbs and fusion proteins other than tumour necrosis alpha (TNF-α) inhibitors, including therapeutics modulating T-cell-mediated pathologies (muromonab, abatacept, belatacept, ipilimumab, basiliximab, daclizumab), inducing lymphopenia (alemtuzumab), depleting CD20+ B cells (rituximab) and interfering with various targets (anakinra, natalizumab, blodalumab, ixekizumab and others) with a focus on children, and to provide a framework of evaluating the risk for IFIs in this population.

Clinical hepatotoxicity associated with antifungal agents.

INTRODUCTION: Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents. Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure. Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.

Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors.

Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population.

Intraventricular Hemorrhage and Platelet Indices in Extremely Premature Neonates.

Intraventricular hemorrhage (IVH) is a multifactorial disorder, the most important risk factors of which are prematurity and low birth weight. Disturbances in cerebral blood flow, inherent fragility of the germinal matrix vasculature, and platelet/coagulation disturbances are the 3 major pathogenic mechanisms. In this context, we investigated the role of platelet indices and several maternal and neonatal characteristics in the development of IVH through a retrospective cohort analysis of 130 extremely premature neonates, 24% of whom presented with severe IVH. There was a significant difference in platelet counts between the IVH and the control group on the first day of life (P=0.046). Presence of IVH was linked with lower birth weight (P=0.006) and lower gestational age (P=0.001). Platelet count on the first day of life was positively correlated with survival (P=0.001) and, along with platelet mass, was indicative of the worst IVH grade recorded for each neonate (P=0.002 and 0.007, respectively). Prolonged prothrombin time was also correlated with IVH (P<0.001), but factor analysis supported no prominent role. Maternal medications seem to play a minor role as well. In conclusion, IVH in extremely premature infants cannot be solely explained by platelet parameters, and further studies are required to determine the relationships between IVH, platelet indices, and outcomes.

Intraventricular Hemorrhage and Platelet Indices in Extremely Premature Neonates.

Intraventricular hemorrhage (IVH) is a multifactorial disorder, the most important risk factors of which are prematurity and low birth weight. Disturbances in cerebral blood flow, inherent fragility of the germinal matrix vasculature, and platelet/coagulation disturbances are the 3 major pathogenic mechanisms. In this context, we investigated the role of platelet indices and several maternal and neonatal characteristics in the development of IVH through a retrospective cohort analysis of 130 extremely premature neonates, 24% of whom presented with severe IVH. There was a significant difference in platelet counts between the IVH and the control group on the first day of life (P=0.046). Presence of IVH was linked with lower birth weight (P=0.006) and lower gestational age (P=0.001). Platelet count on the first day of life was positively correlated with survival (P=0.001) and, along with platelet mass, was indicative of the worst IVH grade recorded for each neonate (P=0.002 and 0.007, respectively). Prolonged prothrombin time was also correlated with IVH (P<0.001), but factor analysis supported no prominent role. Maternal medications seem to play a minor role as well. In conclusion, IVH in extremely premature infants cannot be solely explained by platelet parameters, and further studies are required to determine the relationships between IVH, platelet indices, and outcomes.