The lack of either IRF9, or STAT2, has surprisingly little effect on human natural killer cell development and function.

Analysis of genetically defined immunodeficient patients allows study of the effect of the absence of specific proteins on human immune function in real-world conditions. Here we have addressed the importance of type I interferon signalling for human NK cell development by studying the phenotype and function of circulating NK cells isolated from patients suffering primary immunodeficiency disease due to mutation of either the human interferon regulatory factor 9 (IRF9) or the signal transducer and activator of transcription 2 (STAT2) genes. IRF9, together with phosphorylated STAT1 and STAT2, form a heterotrimer called interferon stimulated gene factor 3 (ISGF3) which promotes the expression of hundreds of IFN-stimulated genes that mediate antiviral function triggered by exposure to type I interferons. IRF9- and STAT2-deficient patients are unable to respond efficiently to stimulation by type I interferons and so our experiments provide insights into the importance of type I interferon signalling and the consequences of its impairment on human NK cell biology. Surprisingly, the NK cells of these patients display essentially normal phenotype and function.

A Validated Highly Sensitive Microsatellite Instability Assay Accurately Identifies Individuals Harboring Biallelic Germline PMS2 Pathogenic Variants in Constitutional Mismatch Repair Deficiency.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare and extraordinarily penetrant childhood-onset cancer predisposition syndrome. Genetic diagnosis is often hampered by the identification of mismatch repair (MMR) variants of unknown significance and difficulties in PMS2 analysis, the most frequently mutated gene in CMMRD. We present the validation of a robust functional tool for CMMRD diagnosis and the characterization of microsatellite instability (MSI) patterns in blood and tumors. METHODS: The highly sensitive assessment of MSI (hs-MSI) was tested on a blinded cohort of 66 blood samples and 24 CMMRD tumor samples. Hs-MSI scores were compared with low-pass genomic instability scores (LOGIC/MMRDness). The correlation of hs-MSI scores in blood with age of cancer onset and the distribution of insertion-deletion (indel) variants in microsatellites were analyzed in a series of 169 individuals (n = 68 CMMRD, n = 124 non-CMMRD). RESULTS: Hs-MSI achieved high accuracy in the identification of CMMRD in blood (sensitivity 98.5% and specificity 100%) and detected MSI in CMMRD-associated tumors. Hs-MSI had a strong positive correlation with whole low-pass genomic instability LOGIC scores (r = 0.89, P = 2.2e-15 in blood and r = 0.82, P = 7e-3 in tumors). Indel distribution identified PMS2 pathogenic variant (PV) carriers from other biallelic MMR gene PV carriers with an accuracy of 0.997. Higher hs-MSI scores correlated with younger age at diagnosis of the first tumor (r = -0.43, P = 0.011). CONCLUSIONS: Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

The complex nature of CXCR4 mutations in WHIM syndrome.

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.

Infecciones por virus respiratorio sincitial que requieren hospitalización en pacientes con inmunodeficiencias primarias / Respiratory syncytial virus infections requiring hospitalization in patients with primary immunodeficiency

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 1,6años (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. (AU)

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 1.6years (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. (AU)

Deficiencia de IgA y comorbilidades autoinmunes en la artritis idiopática juvenil / IgA deficiency and autoimmune comorbidities in juvenile idiopathic arthritis

Objetivos: 1) Describir la prevalencia de deficiencia de IgA (DIgA), uveítis, enfermedad celiaca (EC) y alteraciones tiroideas en una cohorte multicéntrica de pacientes diagnosticados de artritis idiopática juvenil (AIJ), y 2) evaluar si los pacientes con AIJ y DIgA presentan otras enfermedades autoinmunes con más frecuencia que los pacientes con niveles normales de IgA. Métodos: Estudio retrospectivo de una cohorte de pacientes con AIJ en seguimiento en unidades de Reumatología pediátrica en 2 hospitales de Madrid (España). Resultados: Se incluyó a 193 pacientes, de los cuales 123 eran mujeres (64%). La edad media al inicio fue 5,6 años (RIC 2,5-9,7) y la mediana de seguimiento 5,1 años (RIC 2,2-8,1). Las 3 categorías ILAR más frecuentes fueron oligoarticular (53%), poliarticular con factor reumatoide negativo (20%) y artritis relacionada con entesitis (10%). Los niveles séricos de IgA estaban disponibles en 172/193 (89%); 25/172 (15%) tenían DIgA, selectiva (< 7mg/dl, n=8) o parcial (7-69mg/dl, n=17). Todos los pacientes tuvieron revisiones oftalmológicas periódicas. Tuvieron uveítis anterior 18 pacientes (9%), 15/18 crónica y 3/18 aguda. Los niveles séricos de antitransglutaminasa IgA (o IgG en pacientes con DIgA) fueron obtenidos en 135/193 (70%); 4 pacientes (3%) fueron diagnosticados de EC por biopsia (n=3) o por criterios clínicos, serológicos o genéticos (n=1); 2 de ellos tenían DIgA (p=0,12; OR=6,4; IC del 95%, 0,9-47,6). Solo 1/153 (0,7%) tuvo hipertirotropinemia con anticuerpos antitiroideos positivos y requirió tratamiento. Conclusión: Los pacientes con AIJ presentan comorbilidades autoinmunes con frecuencia. La DIgA no parece aumentar su prevalencia, con la posible excepción de la EC. (AU)

Objectives: (1) To describe the prevalence of IgA deficiency (IgAD), uveitis, coeliac disease (CD) and thyroid disorders in a multicentre cohort of patients with juvenile idiopathic arthritis (JIA), and (2) to assess whether patients with JIA and IgAD have additional autoimmune disorders more frequently than patients with JIA and normal serum levels of IgA. Methods: Retrospective chart review of a cohort of patients with JIA managed in the paediatric rheumatology units of 2hospitals in Madrid, Spain. Results: This study included 193 patients, 123 (64%) female. The median age at disease onset was 5.6 years (IQR 2.5–9.7) and the median duration of followup was 5.1 years (IQR 2.2–8.1). The 3most common categories of JIA based on the ILAR classification were oligoarticular (53%), poliartritis RF-negative (20%) and enthesitis-related arthritis (10%). Serum IgA levels were available in 172/193 (89%); 25/172 (15%) had selective (<7mg/dl, n=8) or partial (7-69mg/dl, n=17) IgAD. All patients underwent periodic ophthalmic examinations. Eighteen children (9%) had anterior uveitis, which was chronic in 15 and acute in 3. Serum levels of anti-transglutaminase IgA, or IgG in IgAD were obtained in 135/193 (70%). Four children (3%) were diagnosed with CD either by intestinal biopsy (n=3) or by the combination of characteristic clinical, serological and genetic features (n=1); 2of them had IgAD (OR=6.4; 95% CI, 0.9–47.6; p=.12). Only 1 of these 153 patients (0.7%) had hyperthyrotropinaemia with positive anti-thyroid antibodies and required replacement therapy. Conclusion: Patients with JIA frequently present autoimmune comorbidities. IgAD does not seem to increase their prevalence, with the possible exception of CD. (AU)

Uso de rituximab para trombocitopenia refractaria en pacientes con anticuerpos antifosfolípidos / Rituximab therapy for refractory thrombocytopenia in patients with antiphospholipid antibodies

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Recomendaciones para el diagnóstico, seguimiento y tratamiento de la embarazada y del niño con enfermedad de Chagas / Recommendations for the diagnosis, treatment and follow-up of the pregnant woman and child with Chagas disease

La enfermedad de Chagas en zonas no endémicas, como nuestro país, se adquiere fundamentalmente por transmisión vertical. La prevalencia de la enfermedad en embarazadas latinoamericanas oscila entre el 0,7 y el 54% en función del país de origen, la procedencia rural o la edad de la madre, situándose la tasa de transmisión vertical entre el 5 y el 6%. Se sabe que el tratamiento en fases precoces y en concreto en el niño < 15 años tiene altas tasas de curación y parece que el tratamiento de la embarazada tras el parto podría prevenir la transmisión en otros embarazos. Todo ello justificaría el diagnóstico y tratamiento precoz de esta entidad en ambos grupos. En este documento se exponen las recomendaciones actuales de diagnóstico y tratamiento de la enfermedad en el niño y la embarazada. Estas recomendaciones han sido elaboradas por un grupo de trabajo formado por especialistas en Enfermedades Infecciosas, Microbiología Clínica, Ginecología y Pediatría (AU)

Congenital transmission of Chagas disease now occurs in areas where the disease is non-endemic, and also from one generation to another. According to epidemiological data from Latin America, the prevalence of the disease in pregnant women is 0.7%-54%, and the prevalence of vertical transmission is around 5%-6%.Congenital T. cruzi infection is an acute infection in newborns that should be treated with anti-parasitic therapy. The treatment of pregnant women could also have an impact on the control of the disease. This article has been prepared following the recommendations suggested by a group of experts in Infectious Diseases, Microbiology, Gynaecology and Paediatrics (AU)

Utilidad de la reacción en cadena de la polimerasa en el diagnóstico de neurocisticercosis y tripanosomiasis americana / No disponible

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