RESUMEN
BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis, resulting in 3 million hospitalizations each year worldwide. Nirsevimab is a monoclonal antibody against RSV that has an extended half-life. Its postlicensure real-world effectiveness against RSV-associated bronchiolitis is unclear. METHODS: We conducted a prospective, multicenter, matched case-control study to analyze the effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis in infants younger than 12 months of age. Case patients were infants younger than 12 months of age who were hospitalized for RSV-associated bronchiolitis between October 15 and December 10, 2023. Control patients were infants with clinical visits to the same hospitals for conditions unrelated to RSV infection. Case patients were matched to control patients in a 2:1 ratio on the basis of age, date of hospital visit, and study center. We calculated the effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis (primary outcome) by means of a multivariate conditional logistic-regression model with adjustment for confounders. Several sensitivity analyses were performed. RESULTS: The study included 1035 infants, of whom 690 were case patients (median age, 3.1 months; interquartile range, 1.8 to 5.3) and 345 were matched control patients (median age, 3.4 months; interquartile range, 1.6 to 5.6). Overall, 60 case patients (8.7%) and 97 control patients (28.1%) had received nirsevimab previously. The estimated adjusted effectiveness of nirsevimab therapy against hospitalization for RSV-associated bronchiolitis was 83.0% (95% confidence interval [CI], 73.4 to 89.2). Sensitivity analyses gave results similar to those of the primary analysis. The effectiveness of nirsevimab therapy against RSV-associated bronchiolitis resulting in critical care was 69.6% (95% CI, 42.9 to 83.8) (27 of 193 case patients [14.0%] vs. 47 of 146 matched control patients [32.2%]) and against RSV-associated bronchiolitis resulting in ventilatory support was 67.2% (95% CI, 38.6 to 82.5) (27 of 189 case patients [14.3%] vs. 46 of 151 matched control patients [30.5%]). CONCLUSIONS: In a real-world setting, nirsevimab therapy was effective in reducing the risk of hospitalized RSV-associated bronchiolitis. (Funded by the National Agency for AIDS Research-Emerging Infectious Disease and others; ENVIE ClinicalTrials.gov number, NCT06030505.).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Antivirales , Bronquiolitis Viral , Infecciones por Virus Sincitial Respiratorio , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Bronquiolitis Viral/tratamiento farmacológico , Bronquiolitis Viral/etiología , Bronquiolitis Viral/terapia , Bronquiolitis Viral/virología , Estudios de Casos y Controles , Hospitalización/estadística & datos numéricos , Modelos Logísticos , Estudios Prospectivos , Infecciones por Virus Sincitial Respiratorio/complicaciones , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/terapia , Virus Sincitial Respiratorio Humano , Respiración ArtificialRESUMEN
Ceftazidime-avibactam is a novel cephalosporin/B-lactamase inhibitor developed in the context of increasing resistance. This case reports the pharmacokinetics of ceftazidime-avibactam in a critically ill child under continuous renal replacement (CRRT) therapy for fluid overload. The patient was a 6-month-old female with sepsis due to bloodstream infection to Stenotrophomonas maltophilia following stem cell transplantation for severe combined immunodeficiency. CRRT was started on Day 2. Concentrations have been monitored using liquid chromatography-tandem mass spectrometry. Treatment was given every 8 h with a 2 h infusion of 30-7,5 mg/kg and did not reach pharmacokinetic/pharmacodynamic targets. Total clearance was respectively 1.7 and 3.02 L/h, with CRRT clearance respectively 28.8%-60% for ceftazidime and 14%-33% for avibactam. Those clearances are higher than reported in adult literature leading to a risk of treatment failure and emerging resistance. This supports the benefit of monitoring antimicrobial therapy under CRRT and the necessity to assess higher dosing or continuous infusion of ceftazidime-avibactam.
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Compuestos de Azabiciclo , Terapia de Reemplazo Renal Continuo , Sepsis , Adulto , Humanos , Femenino , Niño , Lactante , Ceftazidima/farmacocinética , Antibacterianos , Enfermedad Crítica/terapia , Combinación de Medicamentos , Sepsis/tratamiento farmacológico , Pruebas de Sensibilidad MicrobianaRESUMEN
We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3-5 days-old and had severe sepsis and liver failure. This new variant, detected in France since April 2022, is still circulating and has caused more fatal neonatal enterovirus infections in 2022 and 2023 (8/496; 1.6%, seven associated with echovirus 11) compared with 2016 to 2021 (7/1,774; 0.4%). National and international alerts are warranted.
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Enfermedades Transmisibles , Infecciones por Echovirus , Infecciones por Enterovirus , Enterovirus , Recién Nacido , Humanos , Masculino , Femenino , Infecciones por Echovirus/diagnóstico , Infecciones por Echovirus/epidemiología , Enterovirus Humano B/genética , Infecciones por Enterovirus/diagnóstico , Infecciones por Enterovirus/epidemiología , Francia/epidemiologíaRESUMEN
BACKGROUND: Fanconi anemia (FA) is an inherited disorder characterized clinically by congenital abnormalities, progressive bone marrow failure (BMF), and a predisposition to malignancy. Gene therapy (GT) of FA, via the infusion of gene-corrected peripheral blood (PB) autologous hematopoietic stem cells (HSCs), may constitute a cure for BMF. GT bypasses the donor restrictions and adverse events associated with allogenic HSC transplantation. However, adequate harvesting of PB-HSCs is a crucial determinant of successful engraftment in gene therapy. Harvesting the low numbers of HSCs in patients with FA is particularly challenging. STUDY DESIGN AND METHODS: This open-label phase I/II trial evaluates the feasibility and safety of co-administration of G-CSF and plerixafor in patients with FA for the mobilization and harvesting of peripheral HSCs, intending to use them in a gene therapy trial. Patients with mutations in the FANCA gene received two subcutaneous injections of G-CSF (6 µg/kg × 2/d from D1 to D8. Plerixafor (0.24 mg/kg/d) was administered 2 h before apheresis (from D5 onward). RESULTS: CD34+ cells were mobilized for four patients quickly but transiently after the plerixafor injection. One patient had a CD34+ cell count of over 100/µl; the mobilization peaked 2 h after the injection and lasted for more than 9 h. There were no short-term adverse events associated with the mobilization or harvesting procedures. CONCLUSION: Our data in patients with FA show that the mobilization of HSCs with G-CSF and plerixafor is safe and more efficient in younger individuals without BMF.
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Anemia de Fanconi , Trasplante de Células Madre Hematopoyéticas , Compuestos Heterocíclicos , Antígenos CD34/metabolismo , Anemia de Fanconi/inducido químicamente , Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética/métodos , Factor Estimulante de Colonias de Granulocitos , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , HumanosRESUMEN
BACKGROUND: Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. CASE REPORT: A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. CONCLUSION: Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
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Artritis Juvenil/cirugía , Trasplante de Médula Ósea , Trasplante de Médula Ósea/métodos , Femenino , Humanos , Lactante , Inducción de RemisiónRESUMEN
BACKGROUND: A recent increase in children admitted with hypotensive shock and fever in the context of the COVID-19 outbreak requires an urgent characterization and assessment of the involvement of SARS-CoV-2 infection. This is a case series performed at 4 academic tertiary care centers in Paris of all the children admitted to the pediatric intensive care unit (PICU) with shock, fever and suspected SARS-CoV-2 infection between April 15th and April 27th, 2020. RESULTS: 20 critically ill children admitted for shock had an acute myocarditis (left ventricular ejection fraction, 35% (25-55); troponin, 269 ng/mL (31-4607)), and arterial hypotension with mainly vasoplegic clinical presentation. The first symptoms before PICU admission were intense abdominal pain and fever for 6 days (1-10). All children had highly elevated C-reactive protein (> 94 mg/L) and procalcitonin (> 1.6 ng/mL) without microbial cause. At least one feature of Kawasaki disease was found in all children (fever, n = 20, skin rash, n = 10; conjunctivitis, n = 6; cheilitis, n = 5; adenitis, n = 2), but none had the typical form. SARS-CoV-2 PCR and serology were positive for 10 and 15 children, respectively. One child had both negative SARS-CoV-2 PCR and serology, but had a typical SARS-CoV-2 chest tomography scan. All children but one needed an inotropic/vasoactive drug support (epinephrine, n = 12; milrinone, n = 10; dobutamine, n = 6, norepinephrine, n = 4) and 8 were intubated. All children received intravenous immunoglobulin (2 g per kilogram) with adjuvant corticosteroids (n = 2), IL 1 receptor antagonist (n = 1) or a monoclonal antibody against IL-6 receptor (n = 1). All children survived and were afebrile with a full left ventricular function recovery at PICU discharge. CONCLUSIONS: Acute myocarditis with intense systemic inflammation and atypical Kawasaki disease is an emerging severe pediatric disease following SARS-CoV-2 infection. Early recognition of this disease is needed and referral to an expert center is recommended. A delayed and inappropriate host immunological response is suspected. While underlying mechanisms remain unclear, further investigations are required to target an optimal treatment.
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Secuencia de Bases , Genes Recesivos , Enfermedades Genéticas Congénitas , Osteopetrosis , Eliminación de Secuencia , Nexinas de Clasificación/genética , Niño , Femenino , Enfermedades Genéticas Congénitas/diagnóstico por imagen , Enfermedades Genéticas Congénitas/genética , Humanos , Osteopetrosis/congénito , Osteopetrosis/diagnóstico por imagenRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on the use of PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (nâ¯=â¯22) or osteopetrosis (nâ¯=â¯5) in a single center. The median age was 1.5 years (range, .2 to 17). HSCT with PTCY was a primary procedure (nâ¯=â¯21) or a rescue procedure after graft failure (nâ¯=â¯6). The conditioning regimen was myeloablative in most primary HSCTs and nonmyeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The 2-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade ≥ II, chronic GVHD, and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were 2 cases of grade III acute GVHD and no extensive cGVHD. The cumulative incidences of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders.
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Ciclofosfamida/administración & dosificación , Enfermedades Genéticas Congénitas/terapia , Trasplante de Células Madre Hematopoyéticas , Enfermedades de Inmunodeficiencia Primaria/terapia , Acondicionamiento Pretrasplante , Adolescente , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/prevención & control , Niño , Preescolar , Femenino , Enfermedades Genéticas Congénitas/epidemiología , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Lactante , Masculino , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Donantes de TejidosRESUMEN
Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient's exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetrance. However, variants frequent in a given exome cohort, but absent or rare in public databases, have also been reported and treated as NPVs, without rigorous exploration. We report the generation of a blacklist of variants frequent within an in-house cohort of 3,104 exomes. This blacklist did not remove known pathogenic mutations from the exomes of 129 patients and decreased the number of NPVs remaining in the 3,104 individual exomes by a median of 62%. We validated this approach by testing three other independent cohorts of 400, 902, and 3,869 exomes. The blacklist generated from any given cohort removed a substantial proportion of NPVs (11-65%). We analyzed the blacklisted variants computationally and experimentally. Most of the blacklisted variants corresponded to false signals generated by incomplete reference genome assembly, location in low-complexity regions, bioinformatic misprocessing, or limitations inherent to cohort-specific private alleles (e.g., due to sequencing kits, and genetic ancestries). Finally, we provide our precalculated blacklists, together with ReFiNE, a program for generating customized blacklists from any medium-sized or large in-house cohort of exome (or other next-generation sequencing) data via a user-friendly public web server. This work demonstrates the power of extracting variant blacklists from private databases as a specific in-house but broadly applicable tool for optimizing exome analysis.
Asunto(s)
Bases de Datos de Ácidos Nucleicos , Exoma , Variación Genética , Genoma Humano , Análisis de Secuencia de ADN , Programas Informáticos , Estudios de Cohortes , Femenino , Humanos , MasculinoRESUMEN
X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of-function and hypomorphic IKBKG (also known as NEMO) mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose 3 boys with EDA-ID died from ID. We identify the same private variant in an intron of IKBKG, IVS4+866 C>T, which was inherited from and occurred de novo in the European mother and Japanese mother, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudoexon (PE) generating a frameshift. Its leakiness accounts for NF-κB activation being impaired but not abolished in the boys' cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell-derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the PE, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK.
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Displasia Ectodérmica , Mutación del Sistema de Lectura , Quinasa I-kappa B , Incontinencia Pigmentaria , Intrones , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Displasia Ectodérmica/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Quinasa I-kappa B/deficiencia , Quinasa I-kappa B/metabolismo , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/patología , Incontinencia Pigmentaria/genética , Incontinencia Pigmentaria/metabolismo , Incontinencia Pigmentaria/patología , Macrófagos/metabolismo , Macrófagos/patología , MasculinoRESUMEN
New-onset autoimmune hemolytic anemia (AIHA) occurs in 2% to 6% of pediatric patients post-hematopoietic stem cell transplantation (HSCT) and is a significant complication. Incomplete immune recovery following HSCT may predispose to immune dysregulation including autoimmune cytopenias. We describe an innovative therapy for AIHA refractory to proteasome inhibition. In potentially life-threatening AIHA in the context of HSCT, daratumumab may be an effective rescue therapy.
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Anemia Hemolítica Autoinmune/terapia , Anticuerpos Monoclonales/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/mortalidad , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Biomarcadores , Preescolar , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Bacteriemia/microbiología , Endocarditis Bacteriana/microbiología , Encefalitis Infecciosa/microbiología , Kingella kingae/aislamiento & purificación , Infecciones por Neisseriaceae/microbiología , Amoxicilina/uso terapéutico , Antibacterianos/uso terapéutico , Bacteriemia/diagnóstico , Bacteriemia/tratamiento farmacológico , Líquido Cefalorraquídeo/microbiología , Ciprofloxacina/uso terapéutico , Combinación de Medicamentos , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/tratamiento farmacológico , Femenino , Humanos , Lactante , Encefalitis Infecciosa/diagnóstico , Encefalitis Infecciosa/tratamiento farmacológico , Imagen por Resonancia Magnética , Infecciones por Neisseriaceae/diagnóstico , Infecciones por Neisseriaceae/tratamiento farmacológico , Tomografía Computarizada por Rayos XRESUMEN
The feasibility and reproducibility of liver stiffness measurements using Supersonic Shear-wave Imaging (SSI) in preterm neonate have not been reported. Our aim was to determine if liver stiffness differs between intra-uterine growth restriction (IUGR) and appropriate for gestational age (AGA) preterm infants with/without cholestasis. We measured liver stiffness (in kPa) in 45 AGA and 18 IUGR preterm infants, and assessed reproducibility in 26 preterms using Intraclass Correlation Coefficients (ICC) and Bland-Altman tests. Liver stiffness values were compared between AGA and IUGR with and without cholestasis and correlated with birth weight. Measurements showed high reproducibility (ICC = 0.94-0.98 for intra-operator, 0.86 for inter-operator) with good agreement (95% limits: -1.24 to 1.24 kPa). During the first postnatal week, liver stiffness was higher in IUGR (7.50 ±1.53 kPa) than in AGA infants (5.11 ±0.80 kPa, p<0.001). After day 8, liver stiffness remained unchanged in AGA but increased progressively in IUGR infants (15.57 ±6.49 kPa after day 21). Liver stiffness was higher in IUGR neonates with cholestasis (19.35 ± 9.80 kPa) than without cholestasis (7.72 ± 1.27 kPa, p<0.001). In conclusion, quantitative liver SSI in preterms is feasible and reproducible. IUGR preterms who will develop cholestasis present high liver stiffness even at birth, before biological cholestasis occurs.