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BackgroundSome regions of Spain are withdrawing their pregnancy screening program for congenital toxoplasmosis (CT). The Spanish Research Network of Congenital Toxoplasmosis (REIV-TOXO) was created to describe the current status of CT in Spain. The aims of this study were to describe the epidemiological and clinical characteristics of CT and to evaluate the effect of prenatal treatment on clinical outcomes to inform decision-making policies.MethodsAmbispective observational study including CT cases recorded in the REIV-TOXO database that includes 122 hospitals (2015-2022). Inclusion criteria were one or more of the following: positive PCR in maternal amniotic fluid; positive Toxoplasma gondii-specific IgM or IgA antibodies at birth; positive PCR in the placenta, newborn blood, urine or CSF; increase of specific IgG levels during infant follow-up; or specific IgG persistence beyond age 12 months.FindingsFifty-six newborns (54 pregnancies) were included. Prenatal screening allowed 92.8% of cases to be identified. The time of maternal infection was well documented in 90.7% of cases, with 61.1% occurring in the third trimester. A total of 66.6% (36/54) pregnant women received antiparasitic treatment: 24/36 spiramycin, 8/36 pyrimethamine, sulfadiazine, and folinic acid, and 4/36 both treatments sequentially. Most cases were asymptomatic at birth (62.5%, 35/56), and 84% (47/56) newborns completed one year of treatment. Median follow-up was 24 months (IQR = 3-72): 14.2% children exhibited new complications, mainly ocular. Newborns born to mothers treated prenatally had four-fold lower risk of CT clinical features at birth (p = 0.03) and six-fold lower risk of further complications during follow-up (p = 0.04) with no treatment-related differences during pregnancy.ConclusionsWhile diagnosis based only on neonatal assessment misses a significant number of CT cases, prenatal screening allows treatment to be started during pregnancy, with better clinical outcomes at birth and during follow-up. REIV-TOXO provides valuable information about CT in Spain, highlighting the need for universal maternal screening.

Abstract Background/Objectives Ataxia telangiectasia (A‐T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A‐T. We aimed to understand the current international practice regarding cancer surveillance in A‐T and agreed‐upon approaches to develop cancer surveillance in A‐T. Design/Methods We used a consensus development method, the e‐Delphi technique, comprising three rounds. Round 1 consisted of a Delphi questionnaire and a survey that collected the details of respondents' professional background, experience, and current practice of cancer surveillance in A‐T. Rounds 2 and 3 were designed based on previous rounds and modified according to the comments made by the panellists. The pre‐specified consensus threshold was ≥75% agreement. Results Thirty‐five expert panellists from 13 countries completed the study. The survey indicated that the current practice of cancer surveillance varies widely between experts and centres'. Consensus was reached that evidence‐based guidelines are needed for cancer surveillance in people with A‐T, with separate recommendations for adults and children. Statements relating to the tests that should be included, the age for starting and stopping cancer surveillance and the optimal surveillance interval were also agreed upon, although in some areas, the consensus was that further research is needed. Conclusion The international expert consensus statement confirms the need for evidence‐based cancer surveillance guidelines in A‐T, highlights key features that the guidelines should include, and identifies areas of uncertainty in the expert community. This elucidates current knowledge gaps and will inform the design of future clinical trials.

Febrile neutropenia is one of the main infectious complications experienced by paediatric patients with blood or solid tumours, which, despite the advances in diagnosis and treatment, are still associated with a significant morbidity and mortality. These patients have several risk factors for infection, chief of which are chemotherapy-induced neutropenia, the disruption of cutaneous and mucosal barriers and the use of intravascular devices. Early diagnosis and treatment of febrile neutropenia episodes based on the patient’s characteristics is essential in patients with blood and solid tumours to improve their outcomes. Therefore, it is important to develop protocols in order to optimise and standardise its management. In addition, the rational use of antibiotics, with careful adjustment of the duration of treatment and antimicrobial spectrum, is crucial to address the increase in antimicrobial drug resistance.The aim of this document, developed jointly by the Spanish Society of Pediatric Infectious Diseases and the Spanish Society of Pediatric Hematology and Oncology, is to provide consensus recommendations for the management of febrile neutropenia in paediatric oncology and haematology patients, including the initial evaluation, the stepwise approach to its treatment, supportive care and invasive fungal infection, which each facility then needs to adapt to the characteristics of its patients and local epidemiological trends. Resumen: La neutropenia febril es una de las principales complicaciones infecciosas que sufren los pacientes pediátricos oncohematológicos, y a pesar los avances en diagnóstico y tratamiento, siguen condicionando una mortalidad y morbilidad significativa. Estos pacientes agrupan una serie de factores de riesgo de infección, donde destaca la neutropenia asociada a quimioterapia, la disrupción de barreras cutáneo-mucosas y el uso de dispositivos intravasculares. El abordaje diagnóstico y terapéutico precoz de los episodios de neutropenia febril en los pacientes oncohematológicos, ajustado a las características individuales de cada paciente, es fundamental para mejorar su pronóstico. Por ello, diseñar protocolos de abordaje, que sistematicen su atención, permite optimizar y homogeneizar su abordaje. Además, racionalizar el uso de los antimicrobianos, ajustando la duración y el espectro de los mismos, es crucial para hacer frente al incremento de resistencias a antimicrobianos.El objetivo de este documento, elaborado entre la Sociedad Española de Infectología Pediátrica y la Sociedad Española de Hematología y Oncología Pediátrica, es dar recomendaciones de consenso sobre el manejo de la neutropenia febril en el paciente oncohematológico, respecto al abordaje inicial, terapia secuencial y de soporte e infección fúngica invasiva, que cada centro debe adaptar a las características de sus pacientes y epidemiología local.

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Introduction: Actions to reduce and optimize antimicrobial use are crucial in the management of infectious diseases to counteract the emergence of short- and long-term resistance. This is particularly important for pediatric patients due to the increasing incidence of serious infections caused by resistant bacteria in this population. The aim of this study was to evaluate the impact of a pediatric antimicrobial stewardship program (PROA-NEN) implemented in a Spanish tertiary hospital by assessing the use of systemic antimicrobials, clinical indicators, antimicrobial resistance, and costs. Methods: In this quasi-experimental, single-center study, we included pediatric patients (0–18 years) admitted to specialized pediatric medical and surgical units, as well as pediatric and neonatal intensive care units, from January 2015 to December 2019. The impact of the PROA-NEN program was assessed using process (consumption trends and prescription quality) and outcome indicators (clinical and microbiological). Antibiotic prescription quality was determined using quarterly point prevalence cross-sectional analyses. Results: Total antimicrobial consumption decreased during the initial three years of the PROA-NEN program, followed by a slight rebound in 2019. This decrease was particularly evident in intensive care and surgical units. Antibiotic use, according to the WHO Access, Watch and Reserve (AWaRe) classification, remained stable during the study period. The overall rate of appropriate prescription was 83.2%, with a significant increase over the study period. Clinical indicators did not substantially change over the study period. Direct antimicrobial expenses decreased by 27.3% from 2015 to 2019. Conclusions: The PROA-NEN program was associated with reduced antimicrobial consumption, improved appropriate use, and decreased costs without compromising clinical and/or microbiological outcomes in patients.

BackgroundAt 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.MethodsWe 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.ResultsIn 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.ConclusionsWe 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.

Abstract Background The increasing use of antifungal drugs (AF) in children and the concern for related adverse events and costs has led to the development of specific AF stewardship programmes (AFS). Studies in adult patients have shown improvements in AF prescription and usage after implementation, but paediatric data are scant. The aim of this PROAFUNGI study was to describe the use and appropriateness of AF in a high complexity paediatric centre. Methods Observational, prospective, single-centre, modified point-prevalence study (11 surveys, July–October 2018), including paediatric (

Syndromic immunodeficiencies are a heterogeneous group of inborn errors of immunity that can affect the development of non-immune organs and systems. The genetic basis of these immunodeficiencies is highly diverse, ranging from monogenic defects to large chromosomal aberrations. Antibody deficiency is the most prevalent immunological abnormality in patients with syndromic immunodeficiencies caused by chromosomal rearrangements, and usually manifests as a common variable immunodeficiency (CVID)-like phenotype. Here we describe a patient with a complex phenotype, including neurodevelopmental delay, dysmorphic features, malformations, and CVID (hypogammaglobulinemia, reduced pre-switch and switch memory B cells, and impaired vaccine response). Microarray-based comparative genomic hybridization (aCGH) revealed a 13-Mb deletion on chromosome 4q22.2-q24 involving 53 genes, some of which were related to the developmental manifestations in our patient. Although initially none of the affected genes could be linked to his CVID phenotype, subsequent reanalysis identified NFKB1 haploinsufficiency as the cause. This study underscores the value of periodic reanalysis of unsolved genetic studies performed with high-throughput technologies (eg, next-generation sequencing and aCGH). This is important because of the ongoing incorporation of new data establishing the relationship between genes and diseases. In the present case, NFKB1 had not been associated with human disease at the time aCGH was performed. Eight years later, reanalysis of the genes included in the chromosome 4 deletion enabled us to identify NFKB1 haploinsufficiency as the genetic cause of our patient’s CVID. In the future, other genes included in the deletion may be linked to human disease, allowing us to better define the molecular basis of our patient’s complex clinical phenotype.

BackgroundTwo years since the onset of the COVID-19 pandemic no predictive algorithm has been generally adopted for clinical management and in most algorithms the contribution of laboratory variables is limited.ObjectivesTo measure the predictive performance of currently used clinical laboratory tests alone or combined with clinical variables and explore the predictive power of immunological tests adequate for clinical laboratories. Methods: Data from 2,600 COVID-19 patients of the first wave of the pandemic in the Barcelona area (exploratory cohort of 1,579, validation cohorts of 598 and 423 patients) including clinical parameters and laboratory tests were retrospectively collected. 28-day survival and maximal severity were the main outcomes considered in the multiparametric classical and machine learning statistical analysis. A pilot study was conducted in two subgroups (n=74 and n=41) measuring 17 cytokines and 27 lymphocyte phenotypes respectively.Findings1) Despite a strong association of clinical and laboratory variables with the outcomes in classical pairwise analysis, the contribution of laboratory tests to the combined prediction power was limited by redundancy. Laboratory variables reflected only two types of processes: inflammation and organ damage but none reflected the immune response, one major determinant of prognosis. 2) Eight of the thirty variables: age, comorbidity index, oxygen saturation to fraction of inspired oxygen ratio, neutrophil-lymphocyte ratio, C-reactive protein, aspartate aminotransferase/alanine aminotransferase ratio, fibrinogen, and glomerular filtration rate captured most of the combined statistical predictive power. 3) The interpretation of clinical and laboratory variables was moderately improved by grouping them in two categories i.e., inflammation related biomarkers and organ damage related biomarkers; Age and organ damage-related biomarker tests were the best predictors of survival, and inflammatory-related ones were the best predictors of severity. 4) The pilot study identified immunological tests (CXCL10, IL-6, IL-1RA and CCL2), that performed better than most currently used laboratory tests.ConclusionsLaboratory tests for clinical management of COVID 19 patients are valuable but limited predictors due to redundancy; this limitation could be overcome by adding immunological tests with independent predictive power. Understanding the limitations of tests in use would improve their interpretation and simplify clinical management but a systematic search for better immunological biomarkers is urgent and feasible.

Objective: We describe and analyze the childhood (

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is characterized by hypercytokinemia leading to overwhelming inflammation. We describe the use of a hemadsorption device as part of the supportive treatment for cytokine storm.

Background: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. Methods: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. Findings: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. Interpretation: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. Funding: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men

A previously healthy 9-year-old girl developed fulminant myocarditis due to severe influenza A infection complicated with methicillin-resistant Staphylococcus aureus pneumonia, requiring extracorporeal membrane oxygenation (ECMO) support. Twelve days after admission, Aspergillus fumigatus was isolated in tracheal aspirate, and 12 h later she suddenly developed anisocoria. Computed tomography (CT) of the head showed fungal brain lesions. Urgent decompressive craniectomy with lesion drainage was performed; histopathology found hyphae in surgical samples, culture-positive for Aspergillus fumigatus (susceptible to azoles, echinocandins, and amphotericin B). Extension workup showed disseminated aspergillosis. After multiple surgeries and combined antifungal therapy (isavuconazole plus liposomal amphotericin B), her clinical course was favorable. Isavuconazole therapeutic drug monitoring was performed weekly. Extensive immunological study ruled out primary immunodeficiencies. Fluorine-18 fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) follow-up showed a gradual decrease in fungal lesions. Influenza-associated pulmonary aspergillosis is well-recognized in critically ill adult patients, but pediatric data are scant. Clinical features described in adults concur with those of our case. Isavuconazole, an off-label drug in children, was chosen because our patient had severe renal failure. To conclude, influenza-associated pulmonary aspergillosis is uncommon in children admitted to intensive care for severe influenza, but pediatricians should be highly aware of this condition to enable prompt diagnosis and treatment.

Abstract Background The current scenario of newborn screening is changing as DNA studies are being included in the programs of several countries. Severe combined immunodeficiency (SCID) disorders can be detected using quantitative PCR assays to measure T‐cell receptor excision circles (TRECs), a byproduct of correct T‐cell development. However, in addition to SCID, other T‐cell‐deficient phenotypes such as 22q11.2 deletion syndrome 22q11.2 duplication syndrome, CHARGE syndrome, and trisomy 21 are detected. Methods We present our experience with the detection of 22q11.2 deletion syndrome and 22q11.2 duplication syndrome in a series of 103,903 newborns included in the newborn screening program of Catalonia (Spain). Results Thirty newborns tested were positive (low TREC levels) and five were found to have copy number variations at the 22q11 region (4 deletions and 1 duplication) when investigated with array comparative genomic hybridization technology and MLPA. Conclusion Newborn screening for SCID enables detection of several conditions, such as 22q syndromes, which should be managed by prompt, proactive approaches with adequate counseling for families by a multidisciplinary team.

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Introduction: The aim of the study was to assess the incidence of hospital admission due to severe acute respiratory infection by respiratory syncytial virus (RSV-ARI) in children with primary immunodeficiencies (PIDs) and the severity of RSV-ARI in these patients. Methods: We conducted a nationwide cross-sectional retrospective and prospective multicentre study in the 2011–2017 period. The study was performed in 15 Spanish hospitals and included children with PID who required hospital admission due to RSV-ARI. Results: Out of 439 patients with PID followed up at participating hospitals, 13 (3%) required hospital admission due to RSV-ARI. The median age of admitted patients was 1.6 years (interquartile range, 0.5−2.2), and 7 were male. The types of PID most frequently associated with admission due to RSV-ARI were combined immunodeficiency (CID; 4/71; 6%) and CID with associated or syndromic features (CIDwASF; 6/147; 4%). Two of the 13 patients were receiving palivizumab for RSV prophylaxis, and 3 received potentially active therapies against RSV during the hospital stay. Viral coinfection was detected in 6 patients, 5 (39%) developed complications, and 4 (31%) required admission to the paediatric intensive care unit. There were no documented RSV-related deaths. Conclusions: In the group of patients with PID, severe RSV infection requiring hospitalization is more frequent in patients with CID and CIDwASF, in whom special efforts should be made to prevent RSV infection. Further studies are needed to confirm these results. Resumen: Introducción: El objetivo del estudio fue evaluar la incidencia de la hospitalización por infección respiratoria aguda (IRA) grave por virus respiratorio sincitial (VRS) en niños con inmunodeficiencia primaria (IDP) y la gravedad de la IRA causada por VRS (IRA-VRS) en estos pacientes. Métodos: Estudio transversal ambispectivo multicéntrico a nivel nacional realizado en el período 2011–2017. El estudio se llevó a cabo en 15 hospitales españoles incluyendo a niños que requirieron hospitalización por IRA-VRS. Resultados: De los 439 pacientes con IDP seguidos en los centros participantes, 13 (3%) fueron ingresados por IRA-VRS. La mediana de edad de los pacientes fue de 1,6 años (rango intercuartílico: 0,5−2,2), y 7 eran varones. Los tipos de IDP asociados con mayor frecuencia a la hospitalización por IRA-VRS fueron la inmunodeficiencia combinada (IDC; 4/71 [6%]) y la IDC con características sindrómicas (IDCCS; 6/147 [4%]). Dos de los 13 pacientes recibían palivizumab para profilaxis frente al VRS, y 3 recibieron terapias potencialmente activas frente al VRS durante la estancia hospitalaria. Se detectó coinfección viral en 6 pacientes, 5 (39%) desarrollaron complicaciones y 4 (31%) requirieron ingreso en la unidad de cuidados intensivos. No se registraron muertes relacionadas con el VRS. Conclusiones: Dentro de los pacientes con IDP, la necesidad de hospitalización por infección grave por VRS es más frecuente en los pacientes con IDC y IDCC, en los que ha de prestarse una atención especial a la prevención de infección por VRS. Se requieren estudios adicionales para confirmar estos resultados.

Resumen: Introducción: El objetivo del estudio fue evaluar la incidencia de la hospitalización por infección respiratoria aguda (IRA) grave por virus respiratorio sincitial (VRS) en niños con inmunodeficiencia primaria (IDP) y la gravedad de la IRA causada por VRS (IRA-VRS) en estos pacientes. Métodos: Estudio transversal ambispectivo multicéntrico a nivel nacional realizado en el período 2011-2017. El estudio se llevó a cabo en 15 hospitales españoles e incluyó a niños que requirieron hospitalización por IRA-VRS. Resultados: De los 439 pacientes con IDP seguidos en los centros participantes, 13 (3%) fueron ingresados por IRA-VRS. La mediana de edad de los pacientes fue de 1,6 años (rango intercuartílico: 0,5-2,2), y 7 eran varones. Los tipos de IDP asociados con mayor frecuencia a la hospitalización por IRA-VRS fueron la inmunodeficiencia combinada (IDC; 4/71 [6%]) y la IDC con características sindrómicas (IDCCS; 6/147 [4%]). Dos de los 13 pacientes recibían palivizumab para profilaxis frente al VRS, y 3 recibieron terapias potencialmente activas frente al VRS durante la estancia hospitalaria. Se detectó coinfección viral en 6 pacientes, 5 (39%) desarrollaron complicaciones y 4 (31%) requirieron ingreso en la unidad de cuidados intensivos. No se registraron muertes relacionadas con el VRS. Conclusiones: Dentro de los pacientes con IDP, la necesidad de hospitalización por infección grave por VRS es más frecuente en los pacientes con IDC y IDCCS, en los que ha de prestarse una atención especial a la prevención de infección por VRS. Se requieren estudios adicionales para confirmar estos resultados. Abstract: Introduction: The aim of the study was to assess the incidence of hospital admission due to severe acute respiratory infection by respiratory syncytial virus (RSV-ARI) in children with primary immunodeficiencies (PIDs) and the severity of RSV-ARI in these patients. Methods: We conducted a nationwide cross-sectional retrospective and prospective multicentre study in the 2011-2017 period. The study was performed in 15 Spanish hospitals and included children with PID who required hospital admission due to RSV-ARI. Results: Out of 439 patients with PID followed up at participating hospitals, 13 (3%) required hospital admission due to RSV-ARI. The median age of admitted patients was 1.6 years (interquartile range, 0.5-2.2), and 7 were male. The types of PID most frequently associated with admission due to RSV-ARI were combined immunodeficiency (CID; 4/71 [6%]) and CID with associated or syndromic features (CIDwASF; 6/147 [4%]). Two of the 13 patients were receiving palivizumab for RSV prophylaxis, and 3 received potentially active therapies against RSV during the hospital stay. Viral coinfection was detected in 6 patients, 5 (39%) developed complications, and 4 (31%) required admission to the paediatric intensive care unit. There were no documented RSV-related deaths. Conclusions: In the group of patients with PID, severe RSV infection requiring hospitalization is more frequent in patients with CID and CIDwASF, in whom special efforts should be made to prevent RSV infection. Further studies are needed to confirm these results.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder characterized by impaired apoptotic homeostasis. The clinical characteristics include lymphoproliferation, autoimmunity (mainly cytopenia), and an increased risk of lymphoma. A distinctive biological feature is accumulation (>2.5%) of an abnormal cell subset composed of TCRαβ+ CD4-CD8- T cells (DNTs). The most common genetic causes of ALPS are monoallelic pathogenic variants in the FAS gene followed by somatic FAS variants, mainly restricted to DNTs. Identification of somatic FAS variants has been typically addressed by Sanger sequencing in isolated DNTs. However, this approach can be costly and technically challenging, and may not be successful in patients with normal DNT counts receiving immunosuppressive treatment. In this study, we identified a novel somatic mutation in FAS (c.718_719insGTCG) by Sanger sequencing on purified CD3+ cells. We then followed the evolutionary dynamics of the variant along time with an NGS-based approach involving deep amplicon sequencing (DAS) at high coverage (20,000-30,000x). Over five years of clinical follow-up, we obtained six blood samples for molecular study from the pre-treatment (DNTs>7%) and treatment (DNTs400 variants called. In summary, our study illustrates the evolutionary dynamics of a somatic FAS mutation before and during immunosuppressive treatment. The results show that pathogenic somatic FAS variants can be identified with the use of DAS in whole blood of ALPS patients regardless of their DNT counts.

Summary: Background: Most children and adolescents infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain asymptomatic or develop a mild coronavirus disease 2019 (COVID-19) that usually does not require medical intervention. However, a small proportion of pediatric patients develop a severe clinical condition, multisystem inflammatory syndrome in children (MIS-C). The involvement of epigenetics in the control of the immune response and viral activity prompted us to carry out an epigenomic study to uncover target loci regulated by DNA methylation that could be altered upon the appearance of MIS-C. Methods: Peripheral blood samples were recruited from 43 confirmed MIS-C patients. 69 non-COVID-19 pediatric samples and 15 COVID-19 pediatric samples without MIS-C were used as controls. The cases in the two groups were mixed and divided into discovery (MIS-C = 29 and non-MIS-C = 56) and validation (MIS-C = 14 and non-MIS-C = 28) cohorts, and balanced for age, gender and ethnic background. We interrogated 850,000 CpG sites of the human genome for DNA methylation variants. Findings: The DNA methylation content of 33 CpG loci was linked with the presence of MIS-C. Of these sites, 18 (54.5%) were located in described genes. The top candidate gene was the immune T-cell mediator ZEB2; and others highly ranked candidates included the regulator of natural killer cell functional competence SH2D1B; VWA8, which contains a domain of the Von Willebrand factor A involved in the pediatric hemostasis disease; and human leukocyte antigen complex member HLA-DRB1; in addition to pro-inflammatory genes such as CUL2 and AIM2. The identified loci were used to construct a DNA methylation profile (EPIMISC) that was associated with MIS-C in both cohorts. The EPIMISC signature was also overrepresented in Kawasaki disease patients, a childhood pathology with a possible viral trigger, that shares many of the clinical features of MIS-C. Interpretation: We have characterized DNA methylation loci that are associated with MIS-C diagnosis. The identified genes are likely contributors to the characteristic exaggerated host inflammatory response observed in these patients. The described epigenetic signature could also provide new targets for more specific therapies for the disorder. Funding: Unstoppable campaign of Josep Carreras Leukaemia Foundation, Fundació La Marató de TV3, Cellex Foundation and CERCA Programme/Generalitat de Catalunya.

Invasive fusariosis (IF) is associated with severe neutropenia in patients with concurrent hematologic conditions. We conducted a retrospective observational study to characterize the epidemiology of IF in 18 Spanish hospitals during 2000–2015. In that time, the frequency of IF in nonneutropenic patients increased from 0.08 cases per 100,000 admissions in 2000–2009 to 0.22 cases per 100,000 admissions in 2010–2015. Nonneutropenic IF patients often had nonhematologic conditions, such as chronic cardiac or lung disease, rheumatoid arthritis, history of solid organ transplantation, or localized fusariosis. The 90-day death rate among nonneutropenic patients (28.6%) and patients with resolved neutropenia (38.1%) was similar. However, the death rate among patients with persistent neutropenia (91.3%) was significantly higher. We used a multivariate Cox regression analysis to characterize risk factors for death: persistent neutropenia was the only risk factor for death, regardless of antifungal therapy.

Resumen: Introducción: La incidencia de la enfermedad meningocócica invasiva (EMI) por serogrupo C ha disminuido desde la introducción de la vacunación sistemática el año 2000. El objetivo de este estudio es determinar los casos de EMI diagnosticados desde entonces y los fallos vacunales en los casos por serogrupo C. Pacientes y métodos: Análisis retrospectivo de pacientes diagnosticados de EMI confirmada por cultivo o reacción en cadena de la polimerasa, en un hospital infantil de tercer nivel de Barcelona, entre 2001 y 2018. Se analizó el número de dosis de vacuna recibidas y la edad, recogidos de la historia clínica y del carnet de vacunaciones. Resultados: Se confirmaron 128 casos de EMI (7,1 casos/año; 70,3% en

Introduction: The incidence of serogroup C invasive meningococcal disease (IMD) has decreased since the introduction of systematic vaccination in 2000 The aim of this study is to determine the number serogroup C IMD cases diagnosed since then and the vaccine failures. Patients and methods: A retrospective analysis was performed on patients diagnosed with IMD by culture or polymerase chain reaction (PCR) in a maternity and childhood hospital in Barcelona between 2001 and 2018. An analysis was made of the number of vaccine doses and the age received, as well as on the medical records and vaccine cards. Results: There were 128 confirmed cases of IMD (7.1 cases/year; 70.3 in

Resumen: Introducción: En 2014 se publicó el Documento de Consenso desarrollado por SEIP-SERPE-SEOP para el diagnóstico y el tratamiento de las infecciones osteoarticulares (IOA). En 2015 se constituyó RIOPed como red nacional multidisciplinar para la investigación en IOA. El objetivo del estudio ha sido valorar el grado de adecuación a las recomendaciones establecidas en el consenso durante un año de seguimiento. Material y métodos: Estudio prospectivo multicéntrico nacional realizado entre septiembre de 2015 y septiembre de 2016 en 37 hospitales con inclusión de pacientes menores de 16 años diagnosticados de IOA, confirmada mediante aislamiento microbiológico, o probable: artritis séptica (AS) con > 40.000 leucocitos en líquido sinovial u osteomielitis (OM)/osteoartritis (OA)/espondilodiscitis (ED) con prueba de imagen compatible. Los resultados se compararon con los obtenidos en el estudio retrospectivo realizado entre 2008 y 2012. Resultados: Se incluyeron 255 casos: 131 OM, 79 AS, 30 OA y 15 ED. Respecto a las pruebas complementarias que el consenso consideró de obligada realización, la radiografía se llevó a cabo en el 87,8% de los casos, el hemocultivo en el 91,6% y el cultivo de líquido sinovial en el 99% de AS. Se realizó RM en el 71% de las OM. La elección del tratamiento antibiótico intravenoso empírico se adecuó a las recomendaciones en el 65,1% de los casos, y en el 62,3% para el tratamiento oral. Se llevó a cabo cirugía en el 36,8% de las AS (85,7% artrotomía), con un descenso significativo respecto al estudio retrospectivo (p = 0,014). Solo el 58,5% de casos se ajustaron a las recomendaciones de duración del tratamiento; sin embargo, se comprobó una menor duración del tratamiento intravenoso. Conclusiones: En general, el grado de adecuación a las recomendaciones que marcaron el grupo de expertos es bueno para las pruebas complementarias y aceptable respecto a la elección del tratamiento antibiótico, aun detectándose casi un 40% de inadecuación. Se ha conseguido un descenso de la estancia hospitalaria. Abstract: Introduction: In 2014 the Consensus Document produced by the Spanish Paediatric Societies (SEIP-SERPE-SEOP) was published to help in the diagnosis and treatment of osteoarticular infections (OAI). In 2015 the RIOPed was considered as a multidisciplinary national network for the investigation into OAI. The aim of this study was to assess the level of adaption to the recommendations established in the Consensus during one year of follow-up. Material and methods: A prospective, national multicentre study was carried out in 37 hospitals between September 2015 and September 2016. The study included patients > 16 years-old with a diagnosis of OAI, confirmed by microbiological isolation, or probable: septic arthritis (SA) with > 40,000 white cells in synovial fluid, or osteomyelitis (OM)/spondylodiscitis (SD) with a compatible imaging test. The results were compared with those obtained in a retrospective study conducted between 2008 and 2012. Results: A total of 235 cases were included, of which 131 were OM, 79 SA, 30 OA, and 15 SD. As regards the complementary tests that the Consensus considered mandatory to perform, radiography was carried out on 87.8% of the cases, a blood culture on 91.6%, and culture of the synovial fluid in 99% of SA. A magnetic resonance (MR) was performed on 71% of the OM cases. The choice of intravenous empirical antibiotic treatment was adapted to the recommendations in 65.1% of cases, and in 62.3% for the oral treatment. Surgery was performed in 36.8% of SA cases (85.7% arthrotomy), with a significant decrease compared to the retrospective study (P = .014). Only 58.5% of cases followed the recommendations on the duration of the treatment; however, a lower duration of intravenous treatment was observed. Conclusions: In general, the level of adaptation to the recommendations that were set by the Expert Group, is good for the complementary tests, and acceptable as regards the choice of antibiotic treatment, although inadequate in almost 40% of cases. A decrease in hospital stay was achieved.

Introduction: In 2014 the Consensus Document produced by the Spanish Paediatric Societies (SEIP-SERPE-SEOP) was published to help in the diagnosis and treatment of osteoarticular infections (OAI). In 2015 the RIOPed was considered as a multidisciplinary national network for the investigation into OAI. The aim of this study was to assess the level of adaption to the recommendations established in the Consensus during one year of follow-up. Material and methods: A prospective, national multicentre study was carried out in 37 hospitals between September 2015 and September 2016. The study included patients >16 years-old with a diagnosis of OAI, confirmed by microbiological isolation, or probable: septic arthritis (SA) with >40,000 white cells in synovial fluid, or osteomyelitis (OM)/spondylodiscitis (SD) with a compatible imaging test. The results were compared with those obtained in a retrospective study conducted between 2008 and 2012. Results: A total of 235 cases were included, of which 131 were OM, 79 SA, 30 OA, and 15 SD. As regards the complementary tests that the Consensus considered mandatory to perform, radiography was carried out on 87.8% of the cases, a blood culture on 91.6%, and culture of the synovial fluid in 99% of SA. A magnetic resonance (MR) was performed on 71% of the OM cases. The choice of intravenous empirical antibiotic treatment was adapted to the recommendations in 65.1% of cases, and in 62.3% for the oral treatment. Surgery was performed in 36.8% of SA cases (85.7% arthrotomy), with a significant decrease compared to the retrospective study (P = .014). Only 58.5% of cases followed the recommendations on the duration of the treatment; however, a lower duration of intravenous treatment was observed. Conclusions: In general, the level of adaptation to the recommendations that were set by the Expert Group, is good for the complementary tests, and acceptable as regards the choice of antibiotic treatment, although inadequate in almost 40% of cases. A decrease in hospital stay was achieved. Resumen: Introducción: En 2014 se publicó el Documento de Consenso desarrollado por SEIP-SERPE-SEOP para el diagnóstico y el tratamiento de las infecciones osteoarticulares (IOA). En 2015 se constituyó RIOPed como red nacional multidisciplinar para la investigación en IOA. El objetivo del estudio ha sido valorar el grado de adecuación a las recomendaciones establecidas en el consenso durante un año de seguimiento. Material y métodos: Estudio prospectivo multicéntrico nacional realizado entre septiembre de 2015 y septiembre de 2016 en 37 hospitales con inclusión de pacientes menores de 16 años diagnosticados de IOA, confirmada mediante aislamiento microbiológico, o probable: artritis séptica (AS) con >40.000 leucocitos en líquido sinovial u osteomielitis (OM)/osteoartritis (OA)/espondilodiscitis (ED) con prueba de imagen compatible. Los resultados se compararon con los obtenidos en el estudio retrospectivo realizado entre 2008 y 2012. Resultados: Se incluyeron 255 casos: 131 OM, 79 AS, 30 OA y 15 ED. Respecto a las pruebas complementarias que el consenso consideró de obligada realización, la radiografía se llevó a cabo en el 87,8% de los casos, el hemocultivo en el 91,6% y el cultivo de líquido sinovial en el 99% de AS. Se realizó RM en el 71% de las OM. La elección del tratamiento antibiótico intravenoso empírico se adecuó a las recomendaciones en el 65,1% de los casos, y en el 62,3% para el tratamiento oral. Se llevó a cabo cirugía en el 36,8% de las AS (85,7% artrotomía), con un descenso significativo respecto al estudio retrospectivo (P = ,014). Solo el 58,5% de casos se ajustaron a las recomendaciones de duración del tratamiento; sin embargo, se comprobó una menor duración del tratamiento intravenoso. Conclusiones: En general, el grado de adecuación a las recomendaciones que marcaron el grupo de expertos es bueno para las pruebas complementarias y aceptable respecto a la elección del tratamiento antibiótico, aun detectándose casi un 40% de inadecuación. Se ha conseguido un descenso de la estancia hospitalaria.

Objectives: Current knowledge on infections caused by Scedosporium spp. and Lomentospora prolificans in children is scarce. We therefore aim to provide an overview of risk groups, clinical manifestation and treatment strategies of these infections. Methods: Pediatric patients (age ≤18 years) with proven/probable Scedosporium spp. or L. prolificans infection were identified in PubMed and the FungiScope® registry. Data on diagnosis, treatment and outcome were collected. Results: Fifty-five children (median age 9 years [IQR: 5–14]) with invasive Scedosporium spp. (n = 33) or L. prolificans (n = 22) infection were identified between 1990 and 2019. Malignancy, trauma and near drowning were the most common risk factors. Infections were frequently disseminated. Most patients received systemic antifungal therapy, mainly voriconazole and amphotericin B, plus surgical treatment.Overall, day 42 mortality was 31%, higher for L. prolificans (50%) compared to Scedosporium spp. (18%). L. prolificans infection was associated with a shorter median survival time compared to Scedosporium spp. (6 days [IQR: 3–28] versus 61 days [IQR: 16–148]). Treatment for malignancy and severe disseminated infection were associated with particularly poor outcome (HR 8.33 [95% CI 1.35–51.40] and HR 6.12 [95% CI 1.52–24.66], respectively). Voriconazole use at any time and surgery for antifungal treatment were associated with improved clinical outcome (HR 0.33 [95% CI 0.11–0.99] and HR 0.09 [95% CI 0.02–0.40], respectively). Conclusions: Scedosporium spp. and L. prolificans infections in children are associated with high mortality despite comprehensive antifungal therapy. Voriconazole usage and surgical intervention are associated with successful outcome. Keywords: Scedosporium spp., Lomentospora prolificans, Invasive fungal infections, Pediatric patients, Children, Voriconazole, Surgery, FungiScope® registry

The Sentinel Schools project was designed to monitor and evaluate the epidemiology of COVID-19 in Catalonia, gathering evidence for health and education policies to inform the development of health protocols and public health interventions to control of SARS-CoV-2 infection in schools. The aim of this study was to estimate the prevalence and incidence of SARS-CoV-2 infections and to identify their determinants among students and staff during February to June in the academic year 2020-2021. We performed two complementary studies, a cross-sectional and a longitudinal component, using a questionnaire to collect nominal data and testing for SARS-CoV-2 detection. We describe the results and perform a univariate and multivariate analysis. The initial crude seroprevalence was 14.8% (95% CI: 13.1-16.5) and 22% (95% CI: 18.3-25.8) for students and staff respectively, and the active infection prevalence was 0.7% (95% CI: 0.3-1) and 1.1% (95% CI: 0.1-2). The overall incidence for persons at risk was 2.73 per 100 person-month and 2.89 and 2.34 per 100 person-month for students and staff, respectively. Socioeconomic, self-reported knowledge, risk perceptions and contact pattern variables were positively associated with the outcome while sanitary measure compliance was negatively associated, the same significance trend was observed in multivariate analysis. In the longitudinal component, epidemiological close contact with SARS-CoV-2 infection was a risk factor for SARS-CoV-2 infection while the highest socioeconomic status level was protective as was compliance with sanitary measures. The small number of active cases detected in these schools suggests a low transmission among children in school and the efficacy of public health measures implemented, at least in the epidemiological scenario of the study period. The major contribution of this study was to provide results and evidence that help analyze the transmission dynamic of SARS-CoV-2 and evaluate the associations between sanitary protocols implemented, and measures to avoid SARS-CoV-2 spread in schools.

Zika virus (ZIKV) is a vector-borne flavivirus with a known teratogenic effect, yet the full spectrum has not been delineated. Studies on endemic areas tried to characterize the clinical outcomes of ZIKV intrauterine exposure. We aimed to describe early neurodevelopmental outcomes on prenatally ZIKV-exposed children in a non-endemic ZIKV area. This is a prospective observational cohort study conducted from May 2016 to December 2021 at Hospital Universitari Vall d’Hebron in Barcelona, Catalonia, Spain. We monitored for up to 24 months 152 children extracted from a pregnant women cohort with suspected ZIKV infection; eleven women (11/150; 7.3%) fulfilled the criteria for a confirmed ZIKV infection. Among the 152 children included, we describe two cases of congenital ZIKV syndrome (CZS) born from women with a confirmed ZIKV infection. Additionally, we describe five cases of other potentially ZIKV-related outcomes (OPZROs), all with normal birth cranial circumference and born to women with probable ZIKV infection. The low exposed prevalence of adverse outcomes in asymptomatic children at birth in a non-endemic area suggests that close follow-up should be addressed by primary care pediatricians instead of pediatric specialists. Further studies are needed to assess the effects of ZIKV intrauterine exposure beyond two years of life.

Resumen: Introducción: El objetivo del estudio fue evaluar la seguridad y la eficacia de la combinación de ledipasvir/sofosbuvir en la infección crónica por el genotipo 1 y 4 del virus de la hepatitis C (VHC) en pacientes pediátricos. Métodos: Se incluyó a pacientes de entre 6 y 18 años. La duración y la dosis de los fármacos antivirales se administraron según la edad del paciente, el estadio de fibrosis y los tratamientos previos con interferón pegilado y ribavirina. La variable principal de eficacia fue el porcentaje de pacientes con una respuesta virológica sostenida 12 semanas (RVS12) después del tratamiento. Resultados: Nueve pacientes con una mediana de edad de 14,8 años (8,48-17,91) fueron tratados con combinación de ledipasvir/sofosbuvir. Cinco pacientes habían recibido previamente tratamiento con interferón pegilado + ribavirina. Ocho pacientes tenían algún grado de fibrosis. La mediana de la carga viral previa al tratamiento fue de 6,2 log (5,9-6,8) con negativización del ARN del VHC 6 semanas después de comenzar el tratamiento en el 100% de los pacientes. Todos los pacientes mantuvieron una respuesta viral sostenida a las 12 semanas. Tres pacientes (33,3%) tuvieron algún tipo de efecto adverso (2 dolores de cabeza y un afta oral). La mediana de seguimiento posterior al tratamiento fue de 24 semanas (12-104). Conclusiones: El tratamiento con ledipasvir/sofosbuvir en pacientes pediátricos con infección crónica por VHC de genotipo 1 y 4 es seguro y efectivo con RVS12, similar a lo reportado en adultos. Abstract: Introduction: Hepatitis C virus infection is world health problem. The aim of this study was to assess the safety and efficacy of ledipasvir/sofosbuvir combination in chronic Hepatitis C Virus (HCV) genotype 1 and 4 infection in paediatric patients. Methods: Eligible patients to be treated with ledipasvir/sofosbuvir were patients from 6 to 18 years old with a chronic HCV genotype 1 or 4 infection. The duration and doses of antiviral drugs were changed depending on patient age, fibrosis stage, and PEGylated interferon + ribavirin experience status. The primary efficacy endpoint was the percentage of patients with a sustained virological response 12 weeks post-treatment. Results: A total of nine patients (7 males) with a median age of 14.8 years (8.48-17.91) were treated with ledipasvir/sofosbuvir combination. Five patients received previous treatment with PEGylated interferon + ribavirin during a median of 8.5 months (3-12 months). Eight patients had some degree of fibrosis (1 patient presented with F1, three patients F2, 2 patients F3, and 2 patients F4). The median pre-treatment viral load was 6.2 Log [5.9-6.8] with the HCV RNA becoming negative six weeks after starting the treatment in 100% of the patients. All patients maintained a sustained viral response at 12 weeks. Three patients (33.3%) had some type of adverse effect (2 headache and one oral thrush). The median post-treatment follow-up was 24 weeks (12-104). Conclusions: Treatment with ledipasvir/sofosbuvir in paediatric patients with chronic HCV infection genotype 1 and 4 is safe and effective with SVR12 and similar to those reported in adults.

Introduction: The aim of this study was to assess the safety and efficacy of ledipasvir/sofosbuvir combination in chronic Hepatitis C Virus (HCV) genotype 1 and 4 infection in paediatric patients. Methods: Eligible patients to be treated with ledipasvir/sofosbuvir were patients from 6 to 18 years old with a chronic HCV genotype 1 or 4 infection. The duration and doses of antiviral drugs were changed depending on patient age, fibrosis stage, and PEGylated interferon + ribavirin experience status. The primary efficacy endpoint was the percentage of patients with a sustained virological response 12 weeks posttreatment. Results: A total of nine patients (7 males) with a median age of 14.8 years (8.48–17.91) were treated with ledipasvir/sofosbuvir combination. Five patients received previous treatment with PEGylated interferon + ribavirin during a median of 8.5 months (3–12 months). Eight patients had some degree of fibrosis (1 patient presented with F1, three patients F2, 2 patients F3, and 2 patients F4). The median pre-treatment viral load was 6.2 log [5.9–6.8] with the HCV RNA becoming negative six weeks after starting the treatment in 100% of the patients. All patients maintained a sustained viral response at 12 weeks. Three patients (33.3%) had some type of adverse effect (2 headache and one oral thrush). The median posttreatment follow-up was 24 weeks (12–104). Conclusions: Treatment with ledipasvir/sofosbuvir in paediatric patients with chronic HCV infection genotype 1 and 4 is safe and effective with SVR12 and similar to those reported in adults. Resumen: Introducción: El objetivo del estudio fue evaluar la seguridad y la eficacia de la combinación de ledipasvir/sofosbuvir en la infección crónica por el genotipo 1 y 4 del virus de la hepatitis C (VHC) en pacientes pediátricos. Métodos: Se incluyó a pacientes de entre 6 y 18 años. La duración y la dosis de los fármacos antivirales se administraron según la edad del paciente, el estadio de fibrosis y los tratamientos previos con interferón pegilado y ribavirina. La variable principal de eficacia fue el porcentaje de pacientes con una respuesta virológica sostenida 12 semanas (RVS12) después del tratamiento. Resultados: Nueve pacientes con una mediana de edad de 14,8 años (8,48-17,91) fueron tratados con combinación de ledipasvir/sofosbuvir. Cinco pacientes habían recibido previamente tratamiento con interferón pegilado + ribavirina. Ocho pacientes tenían algún grado de fibrosis. La mediana de la carga viral previa al tratamiento fue de 6,2 log (5,9-6,8) con negativización del ARN del VHC 6 semanas después de comenzar el tratamiento en el 100% de los pacientes. Todos los pacientes mantuvieron una respuesta viral sostenida a las 12 semanas. Tres pacientes (33,3%) tuvieron algún tipo de efecto adverso (2 dolores de cabeza y un afta oral). La mediana de seguimiento posterior al tratamiento fue de 24 semanas (12-104). Conclusiones: El tratamiento con ledipasvir/sofosbuvir en pacientes pediátricos con infección crónica por VHC de genotipo 1 y 4 es seguro y efectivo con RVS12, similar a lo reportado en adultos.