Zoe Dorothea Pana

Non-Aspergillus fungal infections in chronic granulomatous disease

Chronic granulomatous disease (CGD) is a congenital immunodeficiency, characterised by significant infections due to an inability of phagocyte to kill catalase‐positive organisms including certain fungi such as Aspergillus spp. Nevertheless, other more rare fungi can cause significant diseases. This report is a systematic review of all published cases of non‐Aspergillus fungal infections in CGD patients. Analysis of 68 cases of non‐Aspergillus fungal infections in 65 CGD patients (10 females) published in the English literature. The median age of CGD patients was 15.2 years (range 0.1–69), 60% of whom had the X‐linked recessive defect. The most prevalent non‐Aspergillus fungal infections were associated with Rhizopus spp. and Trichosporon spp. found in nine cases each (13.2%). The most commonly affected organs were the lungs in 69.9%. In 63.2% of cases first line antifungal treatment was monotherapy, with amphotericin B formulations being the most frequently used antifungal agents in 45.6% of cases. The overall mortality rate was 26.2%. Clinicians should take into account the occurrence of non‐Aspergillus infections in this patient group, as well as the possibility of a changing epidemiology in fungal pathogens. Better awareness and knowledge of these pathogens can optimise antifungal treatment and improve outcome in CGD patients.

Risk of azole‐enhanced vincristine neurotoxicity in pediatric patients with hematological malignancies: Old problem – New Dilemma

One of the most well‐known drug interactions in pediatric oncology concerns the co‐administration of itraconazole, an antifungal triazole, and vincristine, an antileukemic agent, which seems to enhance the risk of neurotoxicity of the latter, mediated through the cytochrome CYP450 enzyme system. The aim of this article is to review the metabolism of these two drugs, to analyze the published cases with severe triazole‐enhanced vincristine neurotoxicity, to discuss the pathophysiological mechanisms of this adverse effect, and to contribute in understanding the differences in triazole‐vincristine interaction severity. Pediatr Blood Cancer 2011;57:30–35.

Mannose binding lectin and ficolin-2 polymorphisms are associated with increased risk for bacterial infections in children with B acute lymphoblastic leukemia.

We aimed to investigate whether the presence of mannose binding lectin (MBL2), ficolin 2 (FCN2) polymorphisms or the combined deficiency significantly influence the risk and subsequently the frequency of chemotherapy‐induced bacterial infections in children with B acute lymphoblastic leukemia (B‐ALL).

Transient myeloproliferative disorder in a newborn with down syndrome treated with rasburicase for the risk of development of tumor lysis syndrome: A case report

IntroductionTransient myeloproliferative disorder is a hematologic abnormality characterized by an uncontrolled proliferation of myeloblasts in peripheral blood and bone marrow that primarily affects newborns and babies with Down syndrome. Tumor lysis syndrome is rarely associated with transient myeloproliferative disorder.Case presentationTransient myeloproliferative disorder was diagnosed in a seven-day-old baby girl with Down syndrome, who was referred to our department due to hyperleukocytosis. Our patient developed tumor lysis syndrome, successfully treated with rasburicase, as a complication of transient myeloproliferative disorder resulting from rapid degradation of myeloid blasts after initiation of effective chemotherapy.ConclusionsTumor lysis syndrome is rarely reported as a complication of transient myeloproliferative disorder. To the best of our knowledge, this is the first case of a newborn with Down syndrome and transient myeloproliferative disorder treated with rasburicase for developing tumor lysis syndrome.

Peripheral blood lymphocyte recovery and overall survival in pediatric acute lymphoblastic leukemia

To the Editor: We read with great interest two previously published studies by Rabin et al. [1] and Alkayed et al. [2] concerning the prognostic significance of absolute lymphocyte count (ALC) recovery in children with ALL. Previous studies in adults have demonstrated the predictive role of ALC after induction chemotherapy for a range of hematological malignancies, associating ALC with patients’ survival [3–5]. Data regarding the prognostic impact of ALC repopulation following induction chemotherapy or hematopoetic transplantation in the pediatric setting is limited [1,2,6–9]. Most importantly, a systematic review of the literature highlighted a lack of consensus on critical ALC cut off values and revaluation time points (Table I). The aim of the present study was to analyze the impact of ALC on the 5-year OS at three different cut off levels (ALC1,500< or 1,500 cells/ml, ALC1,000< or 1,000 cells/ml and ALC350< or 350 cells/ml, respectively) in children with ALL at Day þ29 after induction chemotherapy [1,7,8]. We retrospectively evaluated 117 children with de novo diagnosis of ALL treated with the BFM/ALLIC 2009 chemotherapy protocol at the Pediatric Hematology Oncology Unit of our Department. According to our results, B-ALL was recorded in 81.2% (95 cases), T-ALL in 17.1% (20 cases), and bi-phenotypic ALL in two cases (1.7%), respectively. The median age at diagnosis was 5.8 years (range: 0.6–17 years). MedianWBC at diagnosis was 12.650 cells/ml (range: 400–560.000 cells/ml). Furthermore, the median WBC at Day þ29 was 2.100 cells/ml for the children with favorable outcome and 3.800 cells/ml for the children with unfavorable outcome, respectively (P1⁄4 0.04). Relapse was recorded in 11.1% (13 cases) and the mortality rate in 9.4% (11 cases), respectively. Median ALC at Day þ29 was 1,003 cells/ml (range: 100–7.130 cells/ml). In particular, the median ALC at Day þ29 was 1,039 cells/ml in children that survived and 520 cells/ml for the children that died (P1⁄4 0.012). The cut off value of ALC 350 cells/ml was associated with a favorable prognosis, with a 5year OS of 92.3% versus 69.2% for ALC <350 cells/ml (HR 2.2, P1⁄4 0.05). For the cut-off values of ALC1,000 and ALC1,500, a statistical significant difference with OS was not observed. According to previous literature, ALC seems to be a simple and powerful prognostic factor for evaluating OS in pediatric patients with ALL after completion of induction therapy or following HSCT (Table I). Partially contradictory results might have been attributed to the variable ALC cut off values used or due to ethnic differences, as mentioned also by Alkayed et al. [2]. In our case series, very low ALC (ALC350) at Dayþ29 remained a significant prognostic factor for OS that is in concordancewith the results of DeAugulo et al. [8]. The future establishment of ALC as prognostic factor might represent a supplementary or even an alternative to MRD risk stratification in ALL, especially in low income countries. This emphasizes the urgent need for further multicentered prospective studies to evaluate firstly the independent prognostic value of ALC and secondly to standardize the appropriate ALC cut off values in pediatric ALL. Emmanuil Hatzipantelis, MD, PHD Pediatric Hematology–Oncology Unit, 2nd Pediatric Department of Aristotle University of Thessaloniki AHEPA General Hospital Thessaloniki, Greece

Fungal Endocarditis in Neonates: A Review of Seventy-one Cases (1971-2013).

Background: Fungal endocarditis (FE) remains an uncommon but life-threatening complication of invasive fungal infections. As data on neonatal FE are scant, we aimed to review all published experience regarding this serious infection. Methods: Neonatal FE cases published in PubMed (1971–2013) as single cases, or case series were identified using the terms “fungal endocarditis, neonates and cardiac vegetation.” Data on predefined criteria including demographics, predisposing factors, mycology, sites of cardiac involvement, therapy and outcome were collected and analyzed. Results: The dataset comprised 71 neonates with FE. Median birth weight was 940 g [interquartile range (IQR): 609], median gestational age 27 weeks (IQR: 6) and median postnatal age at diagnosis 20 days (IQR: 20). Ninety-two percent of the patients were premature. Right atrium was the most common vegetation site (63%). Seventy-one percent of the cases reported were associated with previous central venous catheters. Candida albicans was the most predominant fungal species (59%). Amphotericin B monotherapy was used in 42.2% and fluconazole in 2.8%. Amphotericin B with flucytosine (25.3%) was the most frequent combined regimen. Surgical treatment was conducted in 28%. Overall mortality was 42.2%. Initiation with combined antifungal treatment was associated with lower mortality than monotherapy (24.2% vs. 51.7%, respectively, P = 0.036). Conclusions: Neonatal FE most frequently occurs in very premature infants and is associated with central venous catheters. C. albicans is the predominant fungus. Although outcome has been dismal, it may be improved with combined antifungal therapy.

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.

Clinical Pharmacology of Itraconazole in Children and Adolescents

Invasive fungal infections are recognized as life-threatening complications primarily in immunocompromised patients, including children with primary immunodeficiencies and hematological malignancies. The antifungal triazoles have become extremely useful components of the antifungal armamentarium. They are well tolerated and possess a broad spectrum of activity. Itraconazole was discovered in 1984 and became available for clinical use in 1990. Itraconazole is a broad spectrum, triazole antifungal agent, and class II drug molecule with low solubility and high permeability and several indications in adults. This article provides a brief overview of the pharmacology of itraconazole with focus on the available data in immunocompromised children and adolescents.

Congenital Acute Lymphoblastic Leukemia Case with a Novel t(2:4:11) (p21:q21:q23) Translocation

Herewith, we present a rare case of a 6-day-old male neonate, born at 40 weeks’ gestation, in whom the diagnosis of congenital acute lymphoblastic leukemia (cALL) was established, characterized by the immunophenotype of the most immature B-cell precursors (pro pro-B-ALL). The initial clinical/laboratory manifestations were leucocytosis, hepatosplenomegaly, anemia, thrombocytopenia, cutaneous lesions known as “leukemia cutis,” and CNS involvement. Cytogenetic testing revealed an extremely rare novel complex chromosomal translocation t(2:4:11) (p21:q21:q23) associated with the rearrangement of MLL gene. The child was treated with the chemotherapy protocol INTERFANT ‘99 but one month after birth developed multiple organ failure and died. The cutaneous lesions were located on the right cheek and left forearm and included nontender, magenta tan papules and nodules with sizes ranging from 3.5 to 1.7 cm (Figure 1). The liver was palpable 4 cm while the spleen 5 cm below the costal margins. The history of the child during the antenatal period was uneventful. The mother first trimester TORCH results were negative and there was no history of exposure to radiation or drugs during pregnancy. Laboratory investigations were: hb 13.5 g/dL, hct 40.2%, WBC 169.000/mm 3 (89% lymphoblasts, 5% neutrophils, 6% lymphocytes), and PLT 42.000/mm 3 . The reticulocyte count was 2.5%, and LDH was 2.265 U/L. Blood and urine culture were negative and serologic testing was not indicative of congenital infection with toxoplasma, rubella, CMV, HSV, syphilis, Epstein Barr, HIV, HAV, HBV, and HCV. Chest radiograph and cranial ultrasound were normal. Bone marrow aspiration revealed