Novel frameshift variants expand the map of the genetic defects in IRF2BP2.

Background: At present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations. Methods: We analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families. Results: In this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance. Conclusions: We describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.

Clinical relevance of viral codetection in infants with respiratory syncytial virus bronchiolitis.

INTRODUCTION: Respiratory syncytial virus (RSV) is the main cause of severe bronchiolitis, especially in infants. The aim of this study is to assess whether codetection of RSV and other respiratory viruses could affect the severity of this infection comparing with unique RSV detection. METHODS: A prospective study from 2016 to 2019 including children under 2 years who were admitted in the Emergency Service of the Hospital Universitari Arnau de Vilanova de Lleida (Spain) was performed. Nasopharyngeal samples from all patients were sent to the laboratory for RSV real-time PCR detection (GeneXpert®). A multiplex PCR that detects other respiratory viruses was done in all RSV-positive samples. Patients'medical records were checked to collect clinical data (hospital length of stay, BROSJOD score, ICU admission, need for ventilatory support or transfer to a reference hospital). Patients were divided in two groups: infants with unique RSV detection and infants with viral codetection. Bivariant analyses were performed to analyze the data obtained. RESULTS: During the period of study 437 RSV bronchiolitis were diagnosed. In 199 of them (177/437; 45,5%) another respiratory virus was detected concomitantly. Bivariant analyses do not show statistically significant differences between both groups. CONCLUSIONS: Viral codetection in infants with RSV bronchiolitis is frequent. However, it does not seems to affect the severity of this infection.

Accuracy of Xpert Ultra for the diagnosis of paediatric tuberculosis in a low TB burden country: a prospective multicentre study.

INTRODUCTION: Childhood pulmonary tuberculosis (TB) remains a diagnostic challenge. This study aimed to evaluate the performance of Xpert Ultra for the diagnosis of pulmonary TB in children in a low TB prevalence setting. METHODS: Prospective, multicentre, diagnostic accuracy study. Children with clinical or radiological suspicion of pulmonary TB were recruited at 11 paediatric units in Spain. Up to three gastric or sputum specimens were taken on 3 consecutive days, and analysed by Xpert MTB/RIF, Xpert Ultra and culture in parallel. RESULTS: 86 children were included (median age 4.9 years, IQR 2.0-10.0; 51.2% male). The final diagnosis was pulmonary TB in 75 patients (87.2%); 33 (44.0%) were microbiologically confirmed. A total of 219 specimens, comprising gastric aspirates (n=194; 88.6%) and sputum specimens (n=25; 11.4%), were analysed. Using culture as reference standard and comparing individual specimens, the sensitivity was 37.8% (14/37) for Xpert MTB/RIF and 81.1% (30/37) for Xpert Ultra (p<0.001); specificity was 98.4% (179/182) and 93.4% (170/182), respectively (p=0.02). In the per-patient analysis, considering positive results on any specimen, the sensitivity was 42.9% (9/21) for Xpert MTB/RIF and 81.0% for Xpert Ultra (17/21, p=0.01); specificity was 96.9% (63/65) and 87.7% (57/65, p=0.07), respectively. CONCLUSIONS: In children with pulmonary TB in a low burden setting, Xpert Ultra has significantly higher sensitivity than the previous generation of Xpert assay and only marginally lower specificity. Therefore, in children undergoing evaluation for suspected pulmonary TB, Xpert Ultra should be used in preference to Xpert MTB/RIF whenever possible.

Osteomielitis aguda per Staphylococcus aureus sensible a la meticil·lina productor de leucocidina de Panton-Valentine associada a trombosi venosa i èmbols sèptics pulmonars / Osteomielitis aguda por Staphylococcus Aureus meticilin-sensible productor de leucocidina de Panton-Valentine asociada a trombosis venosa y émbolos sépticos pulmonares / Acute osteomyelitus due to Panton-Valentine leukocidine-producing methicilin-susceptible Staphylococcus Aureus with deep vein thrombosis and pulmonary septic emboli in a child

Introducció: la leucocidina de Panton-Valentine (LPV) és un factor de virulència identificat en infeccions per Staphyloccus aureus (SA), més freqüent en resistents a meticil•lina (MRSA), nosocomials i adults. Es presenta un cas d'osteomielitis aguda (OA) per SA sensible a la meticil•lina (MSSA) productor de LPV adquirit en la comunitat. Cas clínic: nen de 7 anys remès a urgències per febre i dolor de l'extremitat inferior esquerra amb eritema, edema i actitud antiàlgica. Presentava leucocitosi (28.100/mm3), neutrofília (78%) i elevació de la proteïna C reactiva (199 mg/L) i de la procalcitonina (1,86 ng/mL). La ressonància magnètica feta mostrà OA greu de tíbia amb cel•lulitis, miositis i abscés de 18 cm. Va ser intervingut quirúrgicament i s'aillà MSSA productor de LPV a hemocultiu i ma-terial purulent. Es confirmà trombosi venosa profunda po-plítia amb estudi de trombofília i immunitari normals. Presentava condensació pulmonar basal esquerra amb vessament pleural (6 mm) i ecocardiografia normal. Va rebre antibioteràpia endovenosa sis setmanes (més dues més oral) amb bona evolució en el seguiment posterior. Comentaris: els primers casos d'OA per MSSA productor de LPV en edat pediàtrica al nostre país es van publicar l'any 2011. S'alerta de la possibilitat d'emergència d'aquest gèrmen com a productor d'OA en infants. Està associat a malaltia més greu, resposta sistèmica més extensa i risc de trombosi. Requereix antibioteràpia més perllongada, més necessitat de cirurgia i més risc de complicacions. La tríada OA, trombosi venosa profunda i èmbols sèptics pulmonars és característica i cal un alt índex de sospita per fer un abordatge i un tractament precoços

Introducción. La leucocidina de Panton-Valentine (LPV) es un factor de virulencia identificado en infecciones por Staphyloccus aureus (SA), más frecuente en resistentes a meticilina (MRSA), nosocomiales y adultos. Se presenta un caso de osteomielitis aguda (OA) por SA meticilin-sensible (MSSA) productor de LPV adquirido en la comunidad. Caso clínico. Niño de 7 años remitido a urgencias por fiebre y dolor de la extremidad inferior izquierda con eritema, edema y actitud antiálgica en flexión y rotación. Presentaba leucocitosis (28.100/ mm3), neutrofilia (78%) y elevación de proteína C reactiva (199 mg/L) y procalcitonina (1,86 ng/mL). La resonancia magnética mostró OA grave de tibia con celulitis, miositis y absceso de 18 cm. Se intervino quirúrgicamente y se aisló MSSA productor de LPV en hemocultivo y material purulento. Se confirmó trombosis venosa profunda poplítea con estudio de trombofilia e immunitario normales. Presentaba condensación pulmonar basal izquierda con derrame pleural (6 mm) y ecocardiografía normal. Recibió antibioterapia endovenosa seis semanas (más dos oral) con buena evolución en el seguimiento posterior. Comentarios. Los primeros casos de OA por MSSA productor de LPV en edad pediátrica en nuestro país se publicaron en el año 2011. Se alerta de la posibilidad de emergencia de este germen como productor de OA en niños. Está asociado a enfermedad más grave, respuesta sistémica más extensa y riesgo de trombosis. Requiere antibioterapia más prolongada, más necesidad de cirugía y mayor riesgo de complicaciones. La tríada OA, trombosis venosa profunda y émbolos sépticos pulmonares es característica y se precisa de un alto índice de sospecha para realizar abordaje y tratamiento precoces (AU)

Introduction. The Panton-Valentine leukocidin (PVL) is a virulence factor identified in Staphylococcus aureus (SA) infections, more commonly in methicillin-resistant (MRSA), nosocomial infections, and adults. We report a case of community acquired acute osteomyelitis (AO) by PVL-producing methicillin-susceptible SA (MSSA). Case report. A 7-year-old boy was referred to the emergency department because of fever and pain in the left lower extremity, with associated erythema and edema. Laboratory evaluation showed leukocytosis (28,100/mm3), neutrophilia (78%), and elevated C-reactive protein (199 mg/L) and procalcitonin (1.86 ng/mL). The magnetic resonance imaging showed severe AO of the tibia with cellulitis, myositis and bone abscess. He underwent surgery and PVL-producing MSSA was isolated from the blood and bone cultures. A popliteal deep vein thrombosis (DVT) was documented, and thrombophilia and immunology work-up were unremarkable. The patient was noted to have left basal pulmonary consolidation with pleural effusion and normal echocardiography. He received intravenous antibiotic therapy for six weeks, followed by two weeks of oral therapy, with a good clinical outcome. Discussion. The first cases of AO by PVL-producing MSSA in children in our country were published in 2011; this prompted concerns about the possible emergence of this new pathogen in AO. This agent is associated with more severe disease, a more extensive systemic involvement, and higher rate of complications, including DVT. It requires prolonged antibiotic therapy and more need for surgery. The occurrence of the triad AO, DVT, and pulmonary septic emboli should cause a high index of suspicion and aid in early diagnosis and treatment (AU)