Level diagnosis and risk factors for permanent reval damage in infants with urinary tract infection

Over the past decades experimental and clinical studies have provided considerable new insight into the pathogenesis of pyelonephritis and clinical scarring. The role of bacterial virulence and host defense factors has been recognized including a greater understanding of the importance of the acute inflammation response associated with both reflux and nonreflux pyelonephritis in the etiology of irreversible renal scarring. The late clinical sequelae of renal scarring are well recognized including hypertension, hyposthenuria, proteinuria eclampsia in pregnancy and in most severe cases chronic renal insufficiency. It is this potential for significant morbidity from Urinary Tract Infections (UTI) in childhood that has led to the current emphasis on early and accurate diagnosis, prompt antibiotic treatment and early evaluation of the urinary tract of infants and young children with documented infections. Accurate diagnosis of acute pyelonephritis (APN) on the basis of classic signs and symptoms is often difficult, particularly in neonates and infants. The great value of DMSA scan in distinguishing pyelonephritis from lower UTI has been recognized and it is now considered the reference method for the diagnosis of renal involvement. However, it is an expensive examination that is not readily available in all centers and it also exposes the patient to radiation. Several studies have attempted to correlate clinical and laboratory parameters with the site of UTI but the results have been conflicting. The clinical parameters and inflammatory markers that primarily have been used as indexes for the differentiation of lower for upper UTI include fever, age, grade of reflux, leucocyte and/or neutrophil count, C- reactive protein, erythrocyte sedimentation rate, Nacetyl- b-glucosamidinidase, b2-microglobulin and procalcitonin. In the present study our aim was to determine the variables that might allow identification of infants at risk for renal lesions after their first time UTI. We focused on infants since this age group presents a high frequency of UTIs and has not been adequately studied in the past. Our prospective study was conducted in 343 infants (boys:193, girls: 150) younger than 12 months (median age 3 months) with first time urinary tract infection. The following variables were correlated with the DMSA scan findings: gender, age and other epidemiologic parameters, family history of UTI or urinary tract disease, body temperature, symptoms, WBC and percentage of polymorphonuclear cells, CRP level, erythrocyte sedimentation rate, bacteriologic data, urinalysis data, blood culture results, therapeutic delay time, duration and route of treatment, use of prophylactic antibiotics, number of recurrences, ultrasound findings, presence and grade of vesicoureteral reflux (VUR) and urine 149 b2-microglobulin, a1 microglobulin, albumin values. For statistical analysis Fisher’s exact test, chi-square test, non parametric Mann Whitney test, Pearson correlation and multiple regression analysis were used. A p-value ?0.05 was considered significant. Nearly half of the infants with a first episode of UTI (50.7%) developed APN and 52% of them developed a renal scar. Age and gender was found to be associated with acute cortical defects as older girls presented a greater frequency of APN. No correlation of age or gender was detected with the presence of permanent renal damage. The presence and the level of fever was related only to APN whereas inflammatation indexes were associated with abnormal DMSA scan during the acute phase of infection but not during follow-up. Urinary b2-microglobulin, a1 microglobulin and albumin were not accurate indexes for the localization of infectious process.Κατά τη διάρκεια των τελευταίων δεκαετιών, πειραματικές και κλινικές μελέτες οδήγησαν σε νέα προσέγγιση σχετικά με την παθογένεση της νεφρικής βλάβης στα παιδιά με ουρολοίμωξη. Έγινε κατανοητός ο ρόλος των βακτηρίων και των αμυντικών μηχανισμών του οργανισμού και έχει αποσαφηνισθεί η σημασία της φλεγμονώδους απάντησης στη ανάπτυξη της «νεφρικής ουλής» σε συνδυασμό με την παρουσία ή όχι κυστεοουρητηρικής παλινδρόμησης (ΚΟΠ). Οι απώτερες επιπλοκές της ουρολοίμωξης που οδηγούν στην ανάγκη για έγκαιρη διάγνωση, θεραπεία και απεικονιστικό έλεγχο δεν είναι τόσο συχνές όσο θεωρούνταν στο παρελθόν και περιλαμβάνουν την υπέρταση, υποσθενουρία, πρωτεiνουρία, τις επιπλοκές στην εγκυμοσύνη και σπάνια τη νεφρική ανεπάρκεια. Η ασφαλής διάκριση του επιπέδου της λοίμωξης με βάση τη συμπτωματολογία και τη φυσική εξέταση δεν είναι δυνατή, ιδιαίτερα σε νεογνά και βρέφη. Ως μέθοδος επιλογής στη διάγνωση της οξείας πυελονεφρίτιδας (ΟΠΝ) έχει επικρατήσει η χρήση του στατικού σπινθηρογραφήματος νεφρών με Tc-99m DMSA. Δυστυχώς όμως το κόστος πραγματοποίησής του δεν είναι αμελητέο ενώ επιπλέον δεν είναι παντού διαθέσιμο και εκθέτει τα παιδιά σε ακτινοβολία. Στο παρελθόν έγιναν αρκετές προσπάθειες για την διαπίστωση παραμέτρων που θα οδηγούσαν στην ασφαλή διάκριση του επιπέδου της ουρολοίμωξης. Μελετήθηκαν η ηλικία, το φύλο, η παρουσία και το ύψος του πυρετού, οι δείκτες φλεγμονής, η ΚΟΠ και ο βαθμός της, καθώς και ένζυμα ή πρωτεΐνες όπως οι N-acetyl-bglucosamidinidase, β2 μικροσφαιρίνη και προκαλσιτονίνη. Δυστυχώς καμμία από αυτές τις παραμέτρους αυτόνομα ή σε συνδυασμό δεν αποδείχθηκαν αξιόπιστες. Στην παρούσα προοπτική μελέτη στόχος μας ήταν να διευκρινίσουμε ποια παιδιά με ουρολοίμωξη βρίσκονται σε κίνδυνο να αναπτύξουν νεφρική βλάβη είτε παροδική κατά τη λοίμωξη είτε μόνιμη. Επικεντρωθήκαμε στα βρέφη που παρουσιάζουν υψηλή συχνότητα ουρολοιμώξεων και επιπλέον δεν έχουν μελετηθεί επαρκώς στο παρελθόν. Η μελέτη περιέλαβε 343 βρέφη (193 αγόρια και 150 κορίτσια) με πρώτο επεισόδιο ουρολοίμωξης και διάμεση τιμή ηλικίας τους 3 μήνες. Στα βρέφη αυτά μελετήσαμε τις ακόλουθες παραμέτρους και τις συσχετίσαμε με τα αποτελέσματα του σπινθηρογραφήματος: ηλικία, φύλο και άλλοι επιδημιολογικοί παράγοντες, οικογενειακό ιστορικό ουρολοίμωξης ή πάθησης του ουροποιητικού, θερμοκρασία σώματος, συμπτωματολογία, αριθμός λευκών αιμοσφαιρίων, αναλογία πολυμορφοπυρήνων, τιμή της C-αντιδρώσας πρωτείνης και της ταχύτητας καθίζησης των ερυθρών, είδος και αριθμός βακτηρίων, αποτέλεσμα της μικροσκοπικής ανάλυσης των ούρων και της καλλιέργειας αίματος και οι β2, α1 μικροσφαιρίνες και η αλβουμίνη των ούρων. Επίσης αξιολογήθηκε η καθυστέρηση στη θεραπεία, η διάρκεια και η οδός της αγωγής, η εμφάνιση 147 υποτροπών, η χρήση αντιβιoτικών ως προφύλαξη, τα απεικονιστικά ευρήματα και ιδιαίτερα η παρουσία και ο βαθμός της ΚΟΠ. Για τη στατιστική ανάλυση εφαρμόσθηκαν οι δοκιμασίες Fisher, chi-square, Mann-Whitney (μη παραμετρική), Pearson correlation, multiple regression analysis. Τιμή p?0.05 θεωρήθηκε ως σημαντική. Τα μισά βρέφη της μελέτης (50.7%) παρουσίασαν ΟΠΝ και τα μισά εξ αυτών (52%) ανέπτυξαν μόνιμη νεφρική βλάβη. Τα κορίτσια παρουσίαζαν αυξημένη συχνότητα ΟΠΝ σε μεγαλύτερες ηλικίες ενώ αντίθετα το φύλο και η ηλικία δε βρέθηκαν να σχετίζονται με τη συχνότητα της μόνιμης νεφρικής βλάβης

Timing of voiding cystourethrography in infants with first time urinary infection

The aim of the study was to evaluate whether the timing of performing a voiding cystourethrography (VCUG) following a first urinary tract infection (UTI) in infants is related to the presence or the severity of vesicoureteral reflux (VUR). A total of 411 children (male 230, female 181) with a first-recognised UTI between ages 15 days and 12 months (median 3 months) underwent a VCUG within 4-81 days (median 9 days) following diagnosis. The presence and the grade of the VUR were compared in two groups: an “early” group in which the VCUG was performed during the first week of the start of treatment and a “late” group in which the examination was performed during the second week or thereafter. The prevalence of VUR in the study cohort was 23.3% (96/411 infants). A VUR was diagnosed in 44 infants in the early group (28%) and in 52 in the late group (21%). Reflux of grade III or higher was seen in 25/44 (57%) of the infants in the early group and in 27/52 (52%) infants in the late group. These differences were not significant. Our results suggest that neither the presence nor the grade of VUR in infants is influenced by the timing of the examination following diagnosis. We therefore recommend that it is better to perform VCUG as soon as possible, provided the inflammation has subsided

Overexpression of the GR Riborepressor LncRNA GAS5 Results in Poor Treatment Response and Early Relapse in Childhood B-ALL

Simple Summary Although childhood acute lymphoblastic leukemia (chALL) management is considered as one of the success stories in modern clinical oncology, the increased incidence of relapse in high-risk patients and the severe toxicity/long-term health effects due to chemotherapy intensity highlight the need for further improvements in patients’ risk stratification and personalized management. Synthetic glucocorticoids (GCs) are the core agents in chALL chemotherapy, exerting their role through the nuclear glucocorticoid receptor (GR), while GAS5 lncRNA suppresses the GCs-GR axis through binding to GR’s DNA binding domain. The objective of the study was the evaluation of GAS5 prognostic utility in chALL. GAS5 overexpression was strongly associated with a higher risk for short-term relapse and poor treatment outcome, independently of patients’ clinicopathological data. Moreover, “GAS5-including” multivariate models resulted in superior risk stratification and clinical benefit for disease prognosis, supporting precision medicine decisions in chALL. Glucocorticoids (GCs) remain the cornerstone of childhood acute lymphoblastic leukemia (chALL) therapy, exerting their cytotoxic effects through binding and activating of the glucocorticoid receptor (GR). GAS5 lncRNA acts as a potent riborepressor of GR transcriptional activity, and thus targeting GAS5 in GC-treated chALL could provide further insights into GC resistance and support personalized treatment decisions. Herein, to study the clinical utility of GAS5 in chALL prognosis and chemotherapy response, GAS5 expression was quantified by RT-qPCR in bone marrow samples of chB-ALL patients at diagnosis (n = 164) and at end-of-induction (n = 109), treated with ALL-BFM protocol. Patients’ relapse and death were used as clinical end-points for survival analysis. Bootstrap analysis was performed for internal validation, and decision curve analysis assessed the clinical net benefit for chALL prognosis. Our findings demonstrated the elevated GAS5 levels in blasts of chALL patients compared to controls and the significantly higher risk for short-term relapse and poor treatment outcome of patients overexpressing GAS5, independently of their clinicopathological data. The unfavorable prognostic value of GAS5 overexpression was strongly validated in the high-risk/stem-cell transplantation subgroup. Finally, multivariate models incorporating GAS5 levels resulted in superior risk stratification and clinical benefit for chALL prognostication, supporting personalized prognosis and precision medicine decisions in chALL

Multifocal Aeromonas Osteomyelitis in a Child with Leukemia.

Aeromonas hydrophila is a Gram negative organism causing both intestinal and extraintestinal disease. The case of a 14-year-old girl with underlying immunodeficiency and leukemia who developed systemic A. hydrophila infection is described in this report. While in deep bone marrow aplasia she developed fever, severe pain in the lower extremities, and swelling of the left femur. Blood culture showed Escherichia coli and A. hydrophila whereas pus culture from the soft tissue swelling showed the presence of A. hydrophila. Imaging studies showed diffuse osteolytic lesions. Patient received 5 months of intravenous and oral antibiotics and she improved clinically whereas the radiology findings persisted

Successful Treatment in a Child with Anaplastic Large Cell Lymphoma and Coexistence of Pulmonary Tuberculosis

A 13-year-old girl was admitted to our department with a history of severe pain of her left axilla and fever. On physical examination, a block of lymph nodes in her left axilla, diffuse papular rash, and red-violet swelling of her supraclavicular and subclavian region were noted. Imaging investigations revealed left axillar and supraclavicular lymphadenopathy and a small nodular shade in the upper lobe of her left lung. A biopsy from an axillary lymph node established the diagnosis of anaplastic large cell lymphoma (ALCL), whereas DNA of Mycobacterium tuberculosis was detected by polymerase chain reaction (PCR) in the same tissue biopsy. Patient was started on chemotherapy for ALCL and achieved remission of all initially involved fields. Nevertheless, two new nodular lesions were detected in the left lower lobe. Biopsy revealed granulomas, and PCR was positive for M. tuberculosis. Our patient received treatment with the combination of isoniazid and rifampin (12 months), pyrazinamide (the first 2 months), and maintenance chemotherapy for her ALCL for one year simultaneously. Four years later, she is disease free for both mycobacterial infection and lymphoma. We are reporting this successful management of mycobacterial infection in a patient with ALCL despite intensive chemotherapy that the patient received at the same time

Multifocal Aeromonas Osteomyelitis in a Child with Leukemia

Aeromonas hydrophila is a Gram negative organism causing both intestinal and extraintestinal disease. The case of a 14-year-old girl with underlying immunodeficiency and leukemia who developed systemic A. hydrophila infection is described in this report. While in deep bone marrow aplasia she developed fever, severe pain in the lower extremities, and swelling of the left femur. Blood culture showed Escherichia coli and A. hydrophila whereas pus culture from the soft tissue swelling showed the presence of A. hydrophila. Imaging studies showed diffuse osteolytic lesions. Patient received 5 months of intravenous and oral antibiotics and she improved clinically whereas the radiology findings persisted

Voriconazole Antifungal Prophylaxis in Children With Malignancies: A Nationwide Study

Background: Antifungal prophylaxis (AFP) is recommended in at-risk hematology-oncology patients. We evaluated the safety of AFP with voriconazole (VRC) in pediatric hematology/oncology patients. Materials and Methods: A retrospective study of VRC AFP in children with malignancies hospitalized in all 7 Greek pediatric hematology/oncology centers during 2008 to 2012 was conducted. Patients’ demographics, outcome, and adverse event (AE) data were recorded. Results: Four hundred twenty-nine VRC AFP courses in 249 patients (median age 6 y, 55% boys) were studied. The most common underlying diseases were acute lymphoblastic leukemia (51%), non Hodgkin lymphoma (8.6%), and acute myeloid leukemia (7.7%). The median number of VRC courses per patient was 1.7, whereas the median VRC dose was 7 mg/kg (range, 5 to 7 mg/kg) every 12 hours. During the last 2 weeks before AFP, 51% of the patients had received corticosteroids, 43% suffered from severe neutropenia, and 17.3% from mucositis. The median duration of VRC AFP was 17 days (range, 1 to 31 d). A single breakthrough fungemia due to Candida glabrata was recorded. Only 1 patient died due to the underlying disease. The most common AEs reported in 70/429 (16.3%) courses with >= 1 AE were elevated liver enzymes (50%), hypokalemia (24.3%), and ophthalmological disorders (14.3%). The median time of AE onset was 5 days (range, 1 to 21 d). Among 70 AEs reported, 38.5%, 48.4%, and 12.8% were of grade I, II, and III, respectively. Conclusions: VRC prophylaxis in pediatric hematology/oncology patients appears to be well tolerated