A Brief Report and Mini-Review of Visceral Leishmaniasis-associated Hemophagocytic Lymphohistiocytosis in Children.

We present the case of a 7-year-old boy who fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH). Prompt visualization of his bone marrow confirmed the diagnosis of visceral leishmaniasis (VL). He responded well to treatment with liposomal amphotericin-B. The patient had a false-negative enzyme-linked immunosorbent assay for Leishmania infantum and a false-positive immunoglobulin M test for Epstein Barr virus (EBV). Because age at presentation is similar in children with VL and familial HLH for whom EBV is the usual trigger, ruling out VL is extremely important because nonspecific serologic tests for EBV can lead to the inappropriate diagnosis of EBV-driven primary HLH and to the administration of unnecessary immunochemotherapy.

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new VHL cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other VHL exons. In this study, we show that the mutations induced a dysregulation of VHL splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in VHL exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.

EBV-related Cold Agglutinin Disease Presenting With Conjugated Hyperbilirubinemia: A Pediatric Case Report and Mini Review.

Hemolytic anemia occurs in only 1% to 3% of hospitalized patients with infectious mononucleosis. The authors describe an 8-year-old girl without cervical lymphadenopathy or splenomegaly, who presented with conjugated hyperbilirubinemia and was diagnosed with cold agglutinin disease caused by an immunoglobulin M autoantibody with anti-i specificity. Acute Epstein-Barr virus infection was confirmed by serologic and molecular methods. She recovered uneventfully after a 3-week course of methylprednisolone. Epstein-Barr virus infection should be considered in any case of hemolytic anemia associated with hepatic dysfunction, especially when direct antiglobulin test is positive for C3d. In these cases, a course of corticosteroids seems safe and may be beneficial.

Candidemia in children: Epidemiology, prevention and management.

Candidemia is the leading cause of invasive fungal infections in hospitalised children. The highest rates of candidemia have been recorded in neonates and infants <1 year of age. Candidemia is more frequent in neonates and young infants than in adults, and is associated with better clinical outcomes, but higher inpatient costs. Over the last 10 years, a declining trend has been noted in the incidence of paediatric candidemia in the US and elsewhere due to the hospital-wide implementation of central-line insertion and maintenance bundles that emphasise full sterile barrier precautions, chlorhexidine skin preparation during line insertion, meticulous site and tubing care, and daily discussion of catheter necessity. Additional interventions aiming at reducing gut-associated candidemia are required in immunocompromised and critically ill children.

Natural History, Pathogenesis, and Treatment of Evans Syndrome in Children.

Primary Evans syndrome (ES) is defined by the concurrent or sequential occurrence of immune thrombocytopenia and autoimmune hemolytic anemia in the absence of an underlying etiology. The syndrome is characterized by a chronic, relapsing, and potentially fatal course requiring long-term immunosuppressive therapy. Treatment of ES is hardly evidence-based. Corticosteroids are the mainstay of therapy. Rituximab has emerged as the most widely used second-line treatment, as it can safely achieve high response rates and postpone splenectomy. An increasing number of new genetic defects involving critical pathways of immune regulation identify specific disorders, which explain cases of ES previously reported as "idiopathic".

Advances in Pediatric Intravenous Iron Therapy.

Iron deficiency anemia (IDA) continues to be very common worldwide. Intravenous (IV) iron is an infrequently used therapeutic option in children with IDA despite numerous studies in adults and several small but notable pediatric studies showing efficacy and safety. Presently, the availability of newer IV iron products allows for replacement of the total iron deficit at a single setting. These products appear safer compared to the high molecular weight iron dextrans of the past. Herein, we review the medical literature and suggest that front line use of IV iron should be strongly considered in diseases associated with IDA in children.

The role of laparoscopy in the identification and management of missing accessory spleens after primary splenectomy: A case report and literature review.

We present a 7-year-old boy with recurrent thrombocytopenia after primary laparoscopic splenectomy for immune thrombocytopenia (ITP). Imaging modalities (ultrasound, computed tomography scan, and scintigraphy) revealed two accessory spleens while the subsequent second laparoscopy revealed 11, which were successfully removed. The relevant medical literature is reviewed, and the value of laparoscopy for chronic ITP is highlighted.

X-linked thrombocytopenia in three males with normal sized platelets due to novel WAS gene mutations.

The authors describe two young brothers and a 12-year-old male with long-standing thrombocytopenia with normal sized platelets, in whom novel mutations of the WAS gene were identified. Their clinical picture and the in vitro assessment of the T-cell function were consistent with X-linked thrombocytopenia (XLT). A high index of suspicion for XLT is required, even in the setting of normal sized platelets for males with affected maternally-related male family members, and males with moderately severe chronic thrombocytopenia that have failed to respond to treatments that are usually effective for immune thrombocytopenia.

Susceptibility of 2,252 Pseudomonas aeruginosa Clinical Isolates Over 4 Years to 9 Antimicrobials in a Tertiary Greek Hospital.

BACKGROUND: We determined the antimicrobial resistance of and changes over time in Pseudomonas aeruginosa isolates from hospitalized patients over the period of 2010-2013, in relation to the patient setting and clinical specimen origin, in a tertiary Greek hospital. METHODS: All P. aeruginosa isolates collected from patients with nosocomial infections were processed and cultured according to routine methods. The Vitek 2 automated system was used for antimicrobial susceptibility testing against 9 antimicrobials. RESULTS: Overall, 2,252 P. aeruginosa isolates were tested, and 1,124 (49.91%) were found to be fully susceptible. Among 1,128 resistant isolates, 638 (56.56%) were resistant to ≥3 classes of antipseudomonal antibiotics. Intensive care unit isolates were significantly more resistant than surgical and medical ward isolates, while blood and urine isolates demonstrated the highest resistance rates. Resistance was highest in 2012 and lowest in 2013. CONCLUSION: Continuous surveillance of antimicrobial resistance is extremely important for controlling P. aeruginosa infections in the hospital setting.

Risk factors for carbapenem-resistant Klebsiella pneumoniae infection/colonization: a case-case-control study.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is increasingly reported worldwide. The aim of the present study was to identify risk factors associated with the development of CRKP infections. A retrospective, case-case-control study was performed at the University Hospital of Heraklion, Greece. The study population included 83 patients from whom CRKP was isolated, 79 from whom carbapenem-sensitive K. pneumoniae (CSKP) was isolated and 161 (control group) from whom K. pneumoniae was not isolated. The median age of CRKP and CSKP patients was 79 (28-101) and 80 (39-97) years, respectively, while that of the controls was 75 (18-100) years. K. pneumoniae was isolated predominantly from urine in both case groups, followed by blood. Independent risk factors for CRKP infection/colonization were admission to ICU (p = 0.004), prior surgical procedure (p = 0.036) and presence of renal disease (p = 0.037), while for CSKP were neurological disease (p = 0.007), and older age (p = 0.011). No association between CRKP and prior antimicrobial exposure was found. Of the entire cohort 40 patients (12%) died; 22 (27%) in the CRKP, 12 (15%) in the CSKP and 6 (4%) in the control group. Isolation of any K. pneumoniae strain was associated with higher mortality compared to the control group (21% vs. 4%; p < 0.005). Mortality was not statistically different between those infected/colonized/with a CRKP or a CSKP strain (p = 0.084). According to these results prior ICU stay, prior surgical procedure and renal disease were independent risk factors for the development of a CRKP infection/colonization.

The effect of maternal flora on Candida colonisation in the neonate.

Colonisation may be the first step for the development of Candida infection. The source of neonatal colonisation is thought to be the hospital environment or the maternal vaginal tract. This study investigated to what extend Candida isolates in neonates are similar to isolates from their mother's vaginal tract. Vaginal samples were collected from 347 pregnant women within 48 h before delivery. Samples from oral and rectal mucosa of their neonates were collected within 24-72 h after delivery, were cultured and yeast species were identified. Antifungal susceptibility tests against six antifungal agents were performed. All paired isolates from mother and infant were genotyped by pulse field gel electrophoresis. A total of 82 mothers and of 16 infants were found colonised by Candida spp. C. albicans was the most common species in pregnant women (n = 68) followed by C. glabrata (n = 11). Only C. albicans was isolated from infants, mainly (14/16) from rectal site. All colonised neonates were born to mothers colonised by C. albicans. Candida genotyping revealed identical strains in all investigated neonate-mother pairs. All isolates were susceptible to amphotericin B. Our findings strongly suggest that vertical transmission has the principal role in the neonatal colonisation by C. albicans in the very first days of life.

Transfusion-related acute lung injury/transfusion-associated circulatory overload in a child with non-transfusion dependent thalassemia and aplastic crisis due to acute parvovirus B19 infection.

We present a never-transfused girl with thalassemia intermedia who was admitted for febrile aplastic crisis due to human parvovirus B19. After a first transfusion of packed red blood cells, she developed pulmonary oedema. She improved with supportive care including the use of intravenous diuretics. Due to severe anaemia, she received a second blood transfusion, antibiotics for febrile neutropenia and intravenous γ globulin for control of the parvovirus infection. She had an uneventful recovery. The first of her male blood donors had an antibody against a patient's human leukocyte antigens type II antigen with a high mean fluorescent intensity. Our patient had clinical features and supportive laboratory evidence for mild transfusion-related acute lung injury (TRALI). However, she also met the criteria for transfusion-associated circulatory overload (TACO). We conclude that our patient likely suffered from TRALI/TACO, a consensus term proposed in 2019 for patients in whom TRALI cannot be distinguished from TACO or in whom both conditions occur simultaneously.

The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

A Narrative Review on the Role of Dalbavancin in the Treatment of Bone and Joint Infections.

Bone and joint infections (BJI) require prolonged antimicrobial treatment, leading to lengthy hospitalizations, high costs, the risk of nosocomial infections, and the development of antimicrobial resistance. Dalbavancin is a novel semisynthetic lipoglycopeptide approved for the treatment of adults and children with acute bacterial skin and skin structure infections. This narrative review aims to summarize the characteristics of dalbavancin and the current scientific evidence regarding its clinical efficacy and safety in the treatment of BJI. A literature search until June 2023 was performed to identify all published research about the role of dalbavancin in the management of BJI. Due to its unique pharmacokinetics characterized by prolonged half-life, high bactericidal activity against most Gram-positive bacteria, a good safety profile, and high tissue penetration, dalbavancin can be a valuable alternative to the treatment of BJI. Clinical studies have shown its non-inferiority compared to conventional therapies in BJI, offering potent activity against key pathogens and an extended dosing interval that may shorten hospitalization. In conclusion, dalbavancin represents a promising treatment option for BJI with a favorable safety profile, but further research in both adults and particularly children, who are ideal candidates for long-acting antibiotics, is necessary to evaluate the role of dalbavancin in BJI.

Ιnterleukin-17A-Enriched Neutrophil Extracellular Traps Promote Immunofibrotic Aspects of Childhood Asthma Exacerbation.

Childhood asthma is a chronic inflammatory airway disorder that can drive tissue remodeling. Neutrophils are amongst the most prominent inflammatory cells contributing to disease manifestations and may exert a potent role in the progression of inflammation to fibrosis. However, their role in asthma exacerbation is still understudied. Here, we investigate the association between neutrophil extracellular traps (NETs) and lung fibroblasts in childhood asthma pathophysiology using serum samples from pediatric patients during asthma exacerbation. Cell-based assays and NETs/human fetal lung fibroblast co-cultures were deployed. Increased levels of NETs and interleukin (IL)-17A were detected in the sera of children during asthma exacerbation. The in vitro stimulation of control neutrophils using the sera from pediatric patients during asthma exacerbation resulted in IL-17A-enriched NET formation. The subsequent co-incubation of lung fibroblasts with in vitro-generated IL-17A-enriched NETs led fibroblasts to acquire a pre-fibrotic phenotype, as assessed via enhanced CCN2 expression, migratory/healing capacity, and collagen release. These data uncover the important pathogenic role of the NET/IL-17A axis in asthma exacerbation, linking lung inflammation to fibroblast dysfunction and fibrosis.

Safety and Efficacy of Immune Checkpoint Inhibitors in Children and Young Adults with Haematological Malignancies: Review and Future Perspectives.

Despite the marked improvement in overall survival rates of paediatric patients with haematological malignancies that has been achieved during the last decades, there is still a pressing need for novel therapeutic approaches for the subset of patients with relapsed or refractory disease. Immune checkpoint inhibitors aim to induce potent anti-tumour immune responses by targeted blocking of inhibitory receptors and have shown promising results in preclinical models and studies on the adult population. However, paediatric malignancies present unique features, and so far, experience with these agents is limited. In the current review, we present an overview of efficacy and safety data from case reports, case series, and clinical trials employing the use of immune checkpoint inhibitors in children, adolescents, and young adults with haematological malignancies. We also discuss new possibilities involving novel targets and combination treatments and provide a summary of the currently registered clinical trials.