Hemodialysis-Associated Immune Dysregulation in SARS-CoV-2-Infected End-Stage Renal Disease Patients.

Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1ß, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1ß and IL-8 and CXCL10 (p < 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection.

Variants in CASP10, a diagnostic challenge: Single center experience and review of the literature.

Autoimmune lymphoproliferative syndrome is a primary immunodeficiency caused by variants in FAS-mediated apoptosis related genes and is characterized by lymphadenopathy, splenomegaly and autoimmunity. A total of six different variants in CASP10 have been described as potential causative of disease, although two of them have recently been considered polymorphisms. The high allele frequency of these variants in healthy population in addition to the broad clinical spectrum of the disease difficult the interpretation of their pathogenicity. Here, we describe the clinical and analytical findings of three new patients carrying variants in CASP10 and summarize 12 more cases from the literature. Autoimmune cytopenias, adenopathies and increment of TCRαß+CD4-CD8- cells have been the most common findings, being possibly the FAS-mediated apoptosis pathway the pathogenic mechanism of this disease. The clinical impact and the consequences of CASP10 variants are not fully elucidated, therefore the description of new cases will contribute to solve this issue.

Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies.

The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients.

Debut neonatal de un síndrome hemofagocítico en paciente con hydrops fetalis: ¿Defecto primario o secundario? / No disponible

El síndrome hemofagocítico (SH) es una manifestación clínica común de un grupo de enfermedades con hallazgos clínicos y de laboratorio similares, como consecuencia de una hiperactivación antigénica derivada de una respuesta inmune inefectiva, que resulta en una tormenta de citoquinas y con una reacción inflamatoria exagerada, que puede comprometer la vida si no se instaura un tratamiento adecuado[6]. El SH posee una de las principales dificultades diagnósticas y terapéuticas debido a la variabilidad en su presentación clínica, así como el grupo heterogéneo de posibles causas congénitas o adquiridas. Presentamos el caso clínico de un lactante de un mes de vida con antecedente de prematuridad e hydrops fetalis inmune por isoinmunización RhD, con sospecha clínica de síndrome hemofagocítico primario (AU)

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Presentation of severe combined immunodeficiency with respiratory syncytial virus and pneumocystis co-infection.

Severe combined immunodeficiency can cause severe, life-threatening viral, bacterial and fungal infections at an early age. We report a case of a 4-month-old boy with co-infection by respiratory syncytial virus and Pneumocystis jiroveci infection that led to recognition of severe combined immunodeficiency.

Clinical and genetic characteristics in a series of haemophagocytic lymphohistiocytosis patients without perforin defects

Aim: Haemophagocytic lymphohistiocytosis (HLH) is characterised by T cell and macrophage activation and excessive production of inflammatory cytokines. Genetic diagnosis is required to discriminate between primary forms (familial HLH, FHL), due to mutations in genes involved in cytolysis, and secondary forms. We aimed to analyse the genes coding for Munc13-4 (UNC13D) and syntaxin-11 (STX11) proteins in search of mutations that might explain HLH in 5 patients without perforin defects. Materials and methods: Perforin expression was evaluated by flow cytometry, sCD25 was measured by ELISA and NK activity was investigated by the conventional functional assay. Coding regions and exons surroundings were sequenced for PRF1, UNC13D and STX11 genes. Results: P1 and P2 developed severe early-onset HLH, P1 died at 6 months. P3, with a sister who died after HLH, responded well to treatment (HLH-2004), and had a second HLH episode two years later. P2 developed HLH at year 7 while in complete remission after lymphoblastic leukaemia. P4 and P5 were brothers who died at 5 and 6 years old due to an HLH and EBV mononucleosis infection. XLP was discarded because P4 was a girl. P1 and P3 showed mutations in UNC13D previously described as pathogenic. There were no changes in STX11.Conclusions: UNC13D mutations were found in 50% of the HLH families without perforin defects and STX11 defects were not detected. These results agree with published series in which mutations in UNC13D explain up to 50% of FHL without PRF1 mutations, supporting a heterogeneous genetic background for this disease (AU)

Objetivo: La linfohistiocitosis hemofagocítica (HLH) se caracteriza por la activación incontrolada de células T y macrófagos y producción excesiva de citoquinas inflamatorias. El diagnóstico genético es necesario para distinguir entre formas primarias (HLH familiar, FHL),debidas a mutaciones en genes implicados en citolisis, y secundarias. Nuestro objetivo es analizar la presencia de mutaciones en los genes que codifican para Munc13-4 (UNC13D) ysintaxina-11 (STX11) en cinco pacientes con HLH no asociado a defecto de perforina. Materiales y métodos: Se evaluó la expresión de perforina por citometría, CD25s por ELISA y la actividad NK con un ensayo funcional. Se secuenciaron los exones y regiones flanqueantes de los genes PRF1, UNC13D y STX11.Resultados: P1 y P2 desarrollaron HLH severo de inicio temprano, P1 falleció con 6 meses. P3,con una hermana fallecida tras HLH, respondió adecuadamente al tratamiento (HLH-2004),presentando un segundo episodio dos años después. P2 desarrolló HLH a los 7 años de edad estando en remisión completa de una leucemia linfoblástica previa. P4 y P5 son hermanos que fallecieron con 5 y 6 años tras HLH y mononucleosis por infección EBV. Se descartó XLP ya que uno de los pacientes era niña. P1 y P3 presentaron mutaciones en UNC13D previamente descritas como patogénicas. No se encontraron alteraciones en STX11.Conclusiones: Se encontraron mutaciones en UNC13D en el 50% de las familias con HLH sin defectos de perforina y no se detectaron defectos en STX11. Este resultado concuerda con series publicadas en las que mutaciones en UNC13D explican hasta el 50% de la FLH sin mutaciones en PRF1, y apoyan una base genética muy heterogénea para esta enfermedad (AU)