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[Purpose] STAT1 gain-of-function (GOF) and dominant-negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors shows promising results in treating STAT1 GOF-associated symptoms while management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients' cells., [Methods] Using flow cytometry, immunoblot, qPCR, and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients, and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine-induced STAT1 signaling in these patients., [Results] DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNγ (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient’ cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients., [Conclusion] In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations., This work was supported by the Job Research Foundation (NY, United States); Consejería de Salud de la Junta de Andalucía (SA0051/2020 to O.N.); Agencia de Innovación y Desarrollo de Andalucía (PI-0184-2018 to P.O.), Instituto de Salud Carlos III, Madrid, Spain [Sara Borrell, CD20/00124 to P.B.L, Juan Rodés JR18/00042 to P.O, FIS PI19/01471].

This study aimed to assess the impact of the introduction of pneumococcal conjugate vaccine 13 (PCV13) on the molecular epidemiology of invasive pneumococcal disease (IPD) in children from Andalusia. A population-based prospective surveillance study was conducted on IPD in children aged, This work was supported by Pfizer (grant 53233485).

Background Cutaneous manifestations have been included in COVID-19 patients’ clinical spectrum. Our objective was to determine the association between skin lesions in children and SARS-CoV2 infection, analyzing others possible infectious/autoimmune etiologies. Material and methods Observational, multicenter, cross-sectional study, about children with skin manifestations from April to May 2020. The diagnosis of SARS-CoV2 was performed by PCR in nasopharyngeal exudate and/or presence of antibodies by serology. Results Sixty-two children were included, 9 (14.5%) presented positive antibodies to SARS-CoV-2, with no positive PCR to SARS-Cov-2 in those patients in whom it was made. Patients with positive serology to SARS-CoV-2 presented chilblains and/or vesicular-bullous skin lesions more frequently (66.7% vs. 24.5%, p = 0.019). Generalized, urticarial and maculopapular rash was more common in patients with negative antibodies (37.7 vs. 0%, p = 0.047), others pathogens were isolated in 41.5% of these patients. There were no significant differences in the positivity for autoantibodies between both groups. Conclusion In our study, the presence of chilblains-like and/or vesicular lesions were significantly related to SARS-CoV2 previous contact.

Resumen: Introducción: La infección por VIH era el principal factor de riesgo para presentar neumonía por Pneumocystis jirovecii (NPJ). En la actualidad, las características clínico-epidemiológicas de la NPJ en niños han cambiado, existiendo pocos estudios en este sentido. Métodos: Realizamos un estudio observacional retrospectivo en pacientes pediátricos diagnosticados de NPJ durante 17 años en un hospital de tercer nivel en España. Resultados: Se recogió a 23 pacientes, de los que 11/23 (47,8%) presentaban enfermedad hematológica, 5/23 (21,7%) inmunodeficiencia primaria y 4/23 (17,4%) infección por VIH. Recibían profilaxis con trimetoprima-sulfametoxazol (TMP-SMX) 11/23 pacientes (47,8%). Todos recibieron tratamiento con TMP-SMX y 18/23 (78,3%), glucocorticoides sistémicos. Fallecieron 6/23 pacientes (26,1%), de los que 1/6 (16,7%) presentaba infección por VIH. En los pacientes no VIH con mayor leucocitosis, mayor retención de CO2 y mayor frecuencia cardíaca al inicio, se evidenció mayor mortalidad, diferencias no objetivadas en pacientes con VIH. No se encontraron diferencias en mortalidad en relación con el factor predisponente, empleo de TMP-SMX ni tratamiento con glucocorticoides. Conclusiones: En la actualidad, los pacientes pediátricos con neoplasias hematológicas constituyen el principal grupo de riesgo de desarrollar NPJ en este grupo etario. No hemos encontrado diferencias de mortalidad entre pacientes con o sin infección por VIH como factor predisponente. Entre los pacientes no VIH la mortalidad fue mayor en aquellos que presentaron mayor leucocitosis, mayor retención de CO2 y mayor frecuencia cardíaca al inicio. No se objetivó mejor pronóstico en pacientes que recibían profilaxis con TMP-SMX previamente al desarrollo de la NPJ ni en los que recibieron glucocorticoides sistémicos como parte del tratamiento. Abstract: Introduction: HIV infection was the main risk of suffering Pneumocystis jirovecii pneumonia (PJP). The clinical-epidemiological characteristics of PJP have currently changed, with there being few studies on this. Methods: A retrospective observational study was carried out on paediatric patients diagnosed with PJP over a 17 year period in a third level hospital in Spain. Results: A total of 23 patients were included, of whom 7/23 (47.8%) suffered a haematological disease, 5/23 (21.7%) a primary immunodeficiency, and 4/23 (17.4%) an HIV infection. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) was received by 11/23 (47.8%) patients. All were treated with TMP-SMX and 18/23 (78.3%) with systemic glucocorticoids. There were 6 (26.1%) deaths, of which one of them (16.7%) suffered an HIV infection. A higher mortality was seen in the non-HIV patients with greater leucocytosis, greater CO2 retention, and a higher heart rate at onset, differences not observed in HIV patients. No differences were found in mortality in relation to the predisposing factor, use of pTMP-SMX, or treatment with glucocorticoids. Conclusions: Paediatric patients with haematological cancers are currently the main risk group of developing PJP in this age group. No differences were found in mortality between patients with or without HIV infection as predisposing factor. The mortality among non-HIV patients was higher in those that had greater leucocytosis, greater CO2 retention, and increased heart rate at onset. A better prognosis was not seen in patients that received prophylaxis with TMP-SMX prior to the development of the PJP, or in those that received glucocorticoids as part of the treatment.

Purpose: STAT1 gain-of-function (GOF) and dominant negative (DN) STAT3 syndromes share clinical manifestations including infectious and inflammatory manifestations. Targeted treatment with Janus-kinase (JAK) inhibitors show promising results in treating STAT1 GOF-associated symptoms whilst management of DN STAT3 patients has been largely supportive. We here assessed the impact of ruxolitinib on the JAK-STAT1/3 pathway in DN STAT3 patients’ cells. Methods: Using flow cytometry, immunoblot, qPCR and ELISA techniques, we examined the levels of basal STAT1 and phosphorylated STAT1 (pSTAT1) of cells obtained from DN STAT3, STAT1 GOF patients and healthy donors following stimulation with type I/II interferons (IFNs) or interleukin (IL)-6. We also describe the impact of ruxolitinib on cytokine-induced STAT1 signaling in these patients.Results: DN STAT3 and STAT1 GOF resulted in a similar phenotype characterized by increased STAT1 and pSTAT1 levels in response to IFNα (CD3+ cells) and IFNg (CD14+ monocytes). STAT1-downstream gene expression and C-X-C motif chemokine 10 secretion were higher in most DN STAT3 patients upon stimulation compared to healthy controls. Ex vivo treatment with the JAK1/2-inhibitor ruxolitinib reduced cytokine responsiveness and normalized STAT1 phosphorylation in DN STAT3 and STAT1 GOF patient’ cells. In addition, ex vivo treatment was effective in modulating STAT1 downstream signaling in DN STAT3 patients.Conclusion: In the absence of effective targeted treatment options for AD-HIES at present, modulation of the JAK/STAT1 pathway with JAK inhibitors may be further explored particularly in those AD-HIES patients with autoimmune and/or autoinflammatory manifestations.

INTRODUCCIÓN: El exantema mucocutáneo inducido por Mycoplasma (EMIM) es una entidad separada del síndrome de Stevens-Johnson(SSJ) y el eritema multiforme (EM), descrita principalmente en adolescentes y en la que predomina la afectación mucosa sobre la cutánea.OBJETIVO: Describir nuestra experiencia en pacientes pediátricos afectos de EMIM.MATERIALES Y MÉTODOS: Estudio descriptivo retrospectivo en menores de 14 años con EMIM entre 2015 - 2020.RESULTADOS: Se diagnosticaron 6 pacientes, agrupándose 5 entre enero-abril de 2019. En 5 casos hubo afectación de mucosa ocular, faríngea y urogenital. Las lesiones cutáneas vesículo-ampollosas fueron las predominantes. En todos se aisló M.pneumoniae. Debido a la afectación mucosa, 4 pacientes precisaron nutrición parenteral y 3 sondaje urinario. En 5 se prescribió tratamiento inmunomodulador con corticoides sistémico e inmunoglobulina intravenosa. La evolución fue favorable y la secuela más frecuente fue la xeroftalmia.CONCLUSIÓN: A pesar de la similitud clínica del EMIM con el SSJ y el EM, debemos sospecharlo en adolescentes con predominio de afectación mucosa. La evolución de nuestros pacientes fue favorable con tratamiento de soporte e inmunomodulador. Son necesarios estudios bien diseñados para establecer que pacientes se benefician de tratamiento con corticoides y/o inmunoglobulina.

Introduction: HIV infection was the main risk of suffering Pneumocystis jirovecii pneumonia (PJP). The clinical-epidemiological characteristics of PJP have currently changed, with there being few studies on this. Methods: A retrospective observational study was carried out on paediatric patients diagnosed with PJP over a 17 year period in a third level hospital in Spain. Results: A total of 23 patients were included, of whom 7/23 (47.8%) suffered a haematological disease, 5/23 (21.7%) a primary immunodeficiency, and 4/23 (17.4%) an HIV infection. Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) was received by 11/23 (47.8%) patients. All were treated with TMP-SMX and 18/23 (78.3%) with systemic glucocorticoids. There were six (26.1%) deaths, of which one of them (16.7%) suffered an HIV infection. A higher mortality was seen in the non-HIV patients with greater leucocytosis, greater CO2 retention, and a higher heart rate at onset, differences not observed in HIV patients. No differences were found in mortality in relation to the predisposing factor, use of pTMP-SMX, or treatment with glucocorticoids. Conclusions: Paediatric patients with haematological cancers are currently the main risk group of developing PJP in this age group. No differences were found in mortality between patients with or without HIV infection as predisposing factor. The mortality among non-HIV patients was higher in those that had greater leucocytosis, greater CO2 retention, and increased heart rate at onset. A better prognosis was not seen in patients that received prophylaxis with TMP-SMX prior to the development of the PJP, or in those that received glucocorticoids as part of the treatment. Resumen: Introducción: La infección por VIH era el principal factor de riesgo para padecer neumonía por Pneumocystis jirovecii (NPJ). En la actualidad, las características clínico-epidemiológicas de la NPJ en niños han cambiado, existiendo pocos estudios en este sentido. Métodos: Realizamos un estudio observacional retrospectivo en pacientes pediátricos diagnosticados de NPJ durante 17 años en un hospital de tercer nivel en España. Resultados: Se recogieron 23 pacientes, de los que 11/23 (47,8%) padecían enfermedad hematológica, 5/23 (21,7%) inmunodeficiencia primaria y 4/23 (17,4%) infección por VIH. Recibía profilaxis con trimetoprim-sulfametoxazol (TMP-SMX) 11/23 pacientes (47,8%). Todos recibieron tratamiento con TMP-SMX y 18/23 (78,3%) glucocorticoides sistémicos. Fallecieron 6/23 pacientes (26,1%), de los que 1/6 (16.7%) padecía infección por VIH. En los pacientes no-VIH con mayor leucocitosis, mayor retención de CO2 y mayor frecuencia cardíaca al debut se evidenció mayor mortalidad, diferencias no objetivadas en pacientes VIH. No se encontraron diferencias en mortalidad en relación con el factor predisponente, empleo de pTMP-SMX ni tratamiento con glucocorticoides. Conclusiones: En la actualidad, los pacientes pediátricos con neoplasias hematológicas constituyen el principal grupo de riesgo de desarrollar NPJ en este grupo etario. No hemos encontrado diferencias de mortalidad entre pacientes con o sin infección por VIH como factor predisponente. Entre los pacientes no VIH la mortalidad fue mayor en aquellos que presentaron mayor leucocitosis, mayor retención de CO2 y mayor frecuencia cardíaca al debut. No se objetivó mejor pronóstico en pacientes que recibían profilaxis con TMP-SMX previamente al desarrollo de la NPJ ni en los que recibieron glucocorticoides sistémicos como parte del tratamiento.

Objectives: To evaluate electrocardiogram markers to predict coronary involvement in patients with Kawasaki disease by assessing measures of ventricular repolarization parameters on the 12-lead electrocardiogram. Study design: This cross-sectional study included 180 Spanish and Japanese patients ≤14 years of age with Kawasaki disease, with or without coronary involvement, from 2011 to 2016. We manually measured the Tp-Te/QT ratio and QTc interval (with Bazett's formula) in 12-lead electrocardiogram in the acute and recovery period and explored their potential association with coronary involvement. Results: No association was found between Tp-Te/QT ratio obtained manually in V5 and V6 leads and coronary involvement in the acute (V5:0.25 [IQR, 0.21-0.27] vs 0.25 [IQR, 0.20-0.27], P = .80; V6:0.24 [IQR, 0.21-0.27] vs 0.25 [IQR, 0.20-0.27], P = .86) or the recovery (V5: 0.23 [IQR, 0.20-0.25] vs 0.23 [IQR, 0.19-0.25], P = .68; V6: 0.23 [IQR, 0.20-0.25] vs 0.23 [IQR, 0.17-0.25], P = .50) period. By contrast, QTc in V5 and V6 was significantly lower in patients with Kawasaki disease and coronary involvement in the acute period (V5: 378 ms [IQR, 364-395 ms] vs 390 ms [IQR, 371-411 ms], P = .04; V6: 377 ms [IQR, 364-392 ms] vs 390 ms [IQR, 371-410 ms], P = .01). A QTc interval of

An update of the Spanish consensus document on the diagnosis and treatment of acute tonsillopharyngitis in 2011 is presented. Clinical scores should not be used to prescribe antibiotics, unless microbiological tests are not available or there is a child at risk of rheumatic fever. There is no score better than those set out in the previous consensus. Microbiological tests are recommended in proposed cases, regardless of the result of the scores. Penicillin is the treatment of choice, prescribed twice a day for 10 days. Amoxicillin is the first alternative, prescribed once or twice a day for the same time. First-generation cephalosporins are the treatment of choice in children with non-immediate reaction to penicillin or amoxicillin. Josamycin and midecamycin are the best options for children with immediate penicillin allergic reactions, when non-beta-lactam antibiotics should be used. In microbiological treatment failure, and in streptococcal carriers, the treatments proposed in the previous consensus are still applicable. Resumen: Se presenta una actualización del documento de consenso sobre el diagnóstico y tratamiento de la faringoamigdalitis aguda, publicado en 2011. Las escalas de predicción clínica no deben ser utilizadas para iniciar antibioterapia, salvo que las pruebas microbiológicas no estén disponibles o exista riesgo de fiebre reumática. No existe ninguna escala que sea mejor que las expuestas en el consenso previo. Se proponen casos en los que se recomienda realizar pruebas microbiológicas, con independencia de los resultados de las escalas. El tratamiento de elección de la faringoamigdalitis estreptocócica es penicilina en dos dosis diarias y durante diez días. Amoxicilina, en una o dos dosis diarias y durante el mismo tiempo, es la primera alternativa terapéutica. Las cefalosporinas de primera generación son el tratamiento de elección en niños con reacción retardada no grave a penicilina o amoxicilina. En reacciones alérgicas inmediatas deben utilizarse antibióticos no betalactámicos, siendo josamicina y diacetil-midecamicina las mejores opciones. En el fracaso terapéutico bacteriológico, y en el estado de portador, los tratamientos planteados en el consenso previo siguen siendo válidos.

T-Helper 17 Cells in Genetic Dermatitis An infant with SAM-like syndrome (severe dermatitis, allergies, and metabolic wasting) was found to have a substantial increase in the number of T-helper 17 ...

Urinary tract infection (UTI) is defined as the growth of microorganisms in a sterile urine culture in a patient with compatible clinical symptoms. The presence of bacteria without any symptoms is known as asymptomatic bacteriuria, and does not require any treatment. In neonates and infants, fever is the guiding sign to suspecting a UTI. Classic urinary tract symptoms become more important in older children. Urine cultures collected before starting antibiotics is always required for diagnosis. Clean-catch (midstream) specimens should be collected for urine culture. In the case of non-toilet-trained children, specimens must be obtained by urinary catheterisation, or suprapubic puncture in neonates and infants. Specimens collected by urine bag should not be used for urine culture. There are no significant differences in the clinical evolution and prognosis between oral versus short intravenous followed by oral antibiotic. Empirical antibiotic therapy should be guided by local susceptibility patterns. Second-generation cephalosporin (children under 6 years) and fosfomycin trometamol (over 6 years), are the empiric therapy recommended in this consensus. In the case of pyelonephritis, recommended antibiotic treatment are third-generation cephalosporins (outpatient care) or, if admission is required, aminoglycosides. Ampicillin should be added in infants less than 3 months old. Antibiotic de-escalation should be always practiced once the result of the urine culture is known.

Resumen: La infección del tracto urinario se define como el crecimiento de microorganismos en orina recogida de forma estéril, en un paciente con síntomas clínicos compatibles. En ausencia de sintomatología el aislamiento de bacterias en urocultivo se denomina bacteriuria asintomática y no precisa tratamiento. En neonatos y lactantes el signo guía para sospechar una infección del tracto urinario es la fiebre. En niños continentes los síntomas urinarios clásicos cobran mayor importancia. El diagnóstico requiere siempre la recogida de urocultivo previo al inicio de tratamiento antibiótico. En niños continentes la muestra de orina para urocultivo se debe recoger por micción espontánea. En niños no continentes mediante sondaje vesical, pudiendo optar por punción suprapúbica en neonatos y lactantes pequeños. No se debe enviar para urocultivo una muestra recogida mediante bolsa adhesiva. No se han demostrado diferencias significativas en la evolución clínica y desarrollo de secuelas entre la administración antibiótica oral exclusiva frente a la intravenosa de corta duración seguida de administración oral. La selección de la antibioterapia empírica inicial se basará en el patrón local de susceptibilidad. En la cistitis este consenso recomienda el uso empírico de cefalosporinas de segunda generación en menores de 6 años y fosfomicina trometamol en mayores. La antibioterapia empírica recomendada en pielonefritis que no precisan ingreso son las cefalosporinas de tercera generación. En caso de precisar ingreso se recomiendan los aminoglucósidos. En menores de 3 meses se debe añadir ampicilina. Una vez conocido el resultado del cultivo se debe dirigir el tratamiento de continuación, tanto intravenoso como oral. Abstract: Urinary tract infection (UTI) is defined as the growth of microorganisms in a sterile urine culture in a patient with compatible clinical symptoms. The presence of bacteria without any symptoms is known as asymptomatic bacteriuria, and does not require any treatment. In neonates and infants, fever is the guiding sign to suspecting a UTI. Classic urinary tract symptoms become more important in older children. Urine cultures collected before starting antibiotics is always required for diagnosis. Clean-catch (midstream) specimens should be collected for urine culture. In the case of non-toilet-trained children, specimens must be obtained by urinary catheterisation, or suprapubic puncture in neonates and infants. Specimens collected by urine bag should not be used for urine culture. There are no significant differences in the clinical evolution and prognosis between oral versus short intravenous followed by oral antibiotic. Empirical antibiotic therapy should be guided by local susceptibility patterns. Second-generation cephalosporin (children under 6 years) and fosfomycin trometamol (over 6 years), are the empiric therapy recommended in this consensus. In the case of pyelonephritis, recommended antibiotic treatment are third-generation cephalosporins (outpatient care) or, if admission is required, aminoglycosides. Ampicillin should be added in infants less than 3 months old. Antibiotic de-escalation should be always practiced once the result of the urine culture is known.

Introduction: Acute pyelonephritis (APN) is one of the most common causes of serious bacterial infection in infants. Renal scarring is the most prevalent long-term complication. Objectives: To review the incidence of renal scarring within 6 months after an episode of APN in children under 36 months and its relationship with imaging studies, clinical settings, and bacteriology. Method: A retrospective study of previously healthy patients aged one to 36 months, admitted for a first episode of APN, with a minimum follow-up of 6 months. Demographic and clinical variables were collected along with bacteriology, renal and bladder ultrasound scan, voiding cystourethrography, DMSA-scintigraphy, and re-infection events. Results: A total of 125 patients were included in the study, of which 60% were male, the large majority (92%) febrile, and due to Escherichia coli (74.6%). There was a history of prenatal ultrasound scan changes in 15.4%. Ultrasound scan found dilation of the urinary tract in 22.1%. Voiding cystourethrography was performed on 70 patients: 54.3% no abnormalities, 12.8% vesicoureteral reflux (VUR) grade i-iii, and 32.9% iv-v grade VUR. Six patients had iv-v grade VUR with a normal ultrasound scan. Adherence to DMSA-scintigraphy at 6 months was only 61% of that indicated. Renal scarring was found in 44.3% of those in which it was performed (60 cases). Conclusions: Almost half (44%) DMSA-scintigraphy in children aged one to 36 months hospitalised for APN show renal scarring at 6 months, which was found to be associated with the re-infection events and the iv-v grade VUR. There was no relationship between scarring and the bacteriology or the elevations of inflammatory biochemical markers. Resumen: Introducción: Una de las causas más frecuentes de infección bacteriana grave en lactantes es la pielonefritis aguda (PNFA), cuya secuela más prevalente a largo plazo es la instauración de cicatrices renales. Objetivos: Revisar la incidencia de cicatrices renales a los 6 meses de un episodio de PNFA en niños menores de 36 meses y su relación con la clínica, las pruebas de imagen y la bacteriología. Método: Estudio retrospectivo de pacientes de uno a 36 meses previamente sanos ingresados por un primer episodio de PNFA, con un seguimiento mínimo de 6 meses. Se recogieron las variables demográficas junto con bacteriología, ecografía, cistourografía miccional seriada, recidivas y gammagrafía-DMSA. Resultados: Se incluyeron 125 pacientes, 60% varones, la mayoría febriles al ingreso (92%), debido a E. coli (74,6%). Existía antecedente de alteración ecográfica prenatal solo en el 15,4%. La ecografía detectó dilatación de la vía urinaria en el 22,1%. En 70 pacientes se indicó cistourografía miccional seriada: 54,3% sin anomalías, 12,8% con reflujo vesicoureteral (RVU) grado i-iii y 32,9% con RVU iv-v. Seis pacientes presentaban RVU iv-v con ecografías normales. La adherencia a la gammagrafía DMSA a los 6 meses fue solo del 61% de los indicados. De los efectuados (60 casos), en un 44,3% se hallaron cicatrices renales, relacionadas significativamente con la recurrencia y el RVU iv-v, pero no con la bacteriología ni con la elevación de reactantes. Conclusiones: El 44% de las gammagrafías-DMSA de pacientes de uno a 36 meses hospitalizados por PNFA desarrolla cicatrices renales a los 6 meses. Estas se relacionaron con las recurrencias y el RVU grave, pero no con la bacteriología y los reactantes inflamatorios.