A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome.

ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells.

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

Typhoid fever causing haemophagocytic lymphohistiocytosis in a non-endemic country - first case report and review of the current literature / Fiebre tifoidea como causa de linfohistiocitosis hemofagocítica en un país no endémico: primer caso reportado y revisión de la literatura

Introduction: Development of secondary haemophagocytic lymphohistiocytosis (sHLH) in the context of typhoid fever (TF) is a very rare but serious complication. Methods: Description of the first pediatric case of typhoid fever acquired in a non-endemic area complicated by sHLH. A systematic literature review of sHLH in the context of TF was performed with extraction of epidemiological, clinical and laboratory data. Results: The literature search revealed 17 articles (22 patients). Fifteen patients were eligible for data analysis (53.4% children). All patients had fever and pancytopenia. Transaminases and LDH were frequently elevated (46.6%). Salmonella typhi was detected mainly by blood culture (64.3%). All the patients received antibiotics whereas immunomodulation (dexamethasone) was used in two cases. Conclusions: A high suspicion index for this condition is needed even in non-endemic areas. The addition of immunmodulation to standard antimicrobial therapy should be considered in selected cases

Introducción: El síndrome hemofagocítico (HLH) secundario en el contexto de fiebre tifoidea es una complicación rara pero seria. Métodos: Descripción del primer caso pediátrico de fiebre tifoidea adquirida en área no endémica complicada con síndrome hemofagocítico y revisión sistemática de la literatura de casos de HLH secundarios a fiebre tifoidea. Descripción de datos epidemiológicos, clínicos y de laboratorio, diagnóstico y manejo. Resultados: La búsqueda bibliográfica reveló 17 artículos (22 pacientes). Quince pacientes eran elegibles para el análisis (53,4% niños). La fiebre y la pancitopenia estaban siempre presentes, y las transaminasas y la LDH estaban frecuentemente elevados (46,6%). La detección de S. typhi se realizó mediante hemocultivo, principalmente (64,3%). Todos los pacientes reportados recibieron antibióticos; la dexametasona fue usada como tratamiento inmunomodulador en 2 de los casos. Conclusiones: Mantener alto el grado de sospecha de esta condición es necesario, incluso en áreas no endémicas, ya que el uso de tratamiento inmunomodulador junto al tratamiento antimicrobiano puede ser determinante para una evolución clínica favorable

Clinical practice update of antifungal prophylaxis in immunocompromised children / Revisión de estrategias de profilaxis antifúngica en niños inmunodeprimidos

Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in immunocompromised adults and children. There is a broad group of pediatric patients at risk for IFI in whom primary and/or secondary antifungal prophylaxis (AFP) should be considered despite scant evidence. Pediatric groups at risk for IFI includes extremely premature infants in some settings, while in high-risk children with cancer receiving chemotherapy or undergoing haematopoietic stem cell transplantation (HCT), AFP against yeast and moulds is usually recommended. For solid organ transplanted, children, prophylaxis depends on the type of transplant and associated risk factors. In children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment, AFP depends on the type of immunodeficiency and the degree of immunosuppression. Chronic granulomatous disease is associated with a particular high-risk of IFI and anti-mould prophylaxis is always indicated. In contrast, AFP is not generally recommended in children with long stay in intensive care units. The choice of AFP is limited by the approval of antifungal agents in different age groups and by their pharmacokinetics characteristics. This document aims to review current available information on AFP in children and to provide a comprehensive proposal for each type of patient

Las infecciones fúngicas invasoras (IFI) constituyen un problema creciente en adultos y niños inmunodeprimidos, acompañándose de una elevada morbimortalidad. El número de niños inmunodeprimidos va en aumento. Los grupos de riesgo de IFI en pediatría incluyen a los grandes prematuros, que se benefician de profilaxis con fluconazol, pacientes hemato-oncológicos sometidos a quimioterapia o trasplante de precursores hematopoyéticos con neutropenias prolongadas, en quienes la profilaxis frente a hongos filamentosos suele recomendarse en situaciones de alto riesgo. En niños sometidos a trasplante de órgano sólido, la profilaxis depende del tipo de trasplante y factores de riesgo asociados. En pacientes con inmunodeficiencias primarias o adquiridas como la infección VIH o tratamiento inmunosupresor prolongado, la profilaxis antifúngica dependerá del tipo de inmunodeficiencia primaria y del grado de inmunosupresión. La enfermedad granulomatosa crónica tiene riesgo particularmente elevado de IFI y requiere siempre profilaxis frente a hongos filamentosos. En cambio, en niños con ingresos prolongados en cuidados intensivos la profilaxis frente a IFI habitualmente no está indicada. El tipo de profilaxis está limitado por la diferente aprobación de antifúngicos a distintas edades. Este documento pretende revisar la información actual disponible respecto a profilaxis antifúngica en niños, con propuesta para la estrategia más apropiada en cada tipo de paciente

Executive Summary of the Consensus Document on the Diagnosis and Management of Patients with Primary Immunodeficiencies / Resumen ejecutivo del Documento de consenso sobre diagnóstico y manejo de pacientes con inmunodeficiencias primarias

Primary immunodeficiencies (PIDs) are rare, undiagnosed and potentially fatal diseases. Clinical manifestations of PID can be fatal or leave sequelae that worsen the quality of life of patients. Traditionally, the treatment of PIDs has been largely supportive, with the exception of bone marrow transplantation and, more recently, gene therapy. The discovering of new affected pathways, the development of new molecules and biologics, and the increasing understanding of the molecular basis of these disorders have created opportunities in PIDs therapy. This document aims to review current knowledge and to provide recommendations about the diagnosis and clinical management of adults and children with PIDs based on the available scientific evidence taking in to account current practice and future challenges. A systematic review was conducted, and evidence levels based on the available literature are given for each recommendation where available

Las inmunodeficiencias primarias (IDP) son unas enfermedades raras, frecuentemente infradiagnosticadas y potencialmente fatales. Las manifestaciones clínicas de las IDP pueden ser muy graves y ocasionar secuelas que empeoran la calidad de vida de los pacientes. Tradicionalmente, el tratamiento de las IDP ha sido fundamentalmente de soporte, con excepción del trasplante de progenitores hematopoyéticos y, más recientemente, la terapia génica. El descubrimiento de nuevos mecanismos patogénicos, el desarrollo de nuevas moléculas y fármacos biológicos y los avances en el conocimiento de las bases moleculares de estas enfermedades han abierto oportunidades para el tratamiento de esta afección. El objetivo de este documento es revisar el conocimiento actual y aportar recomendaciones para el diagnóstico y el tratamiento clínico de los pacientes adultos y pediátricos con IDP basado en la evidencia científica disponible y teniendo en cuenta la actual práctica y los retos futuros. Se realizó una revisión sistemática, que justifica los niveles de evidencia para cada recomendación