Resolution of recurrent pediatric acute liver failure with liver transplantation in a patient with NBAS mutation.

BACKGROUND: Pediatric acute liver failure (PALF) remains an enigmatic process of rapid end-organ dysfunction associated with a variety of pathologic conditions though the predominant cause is indeterminate. A growing body of research has identified mutations in the NBAS gene to be associated with recurrent acute liver failure and multi-systemic disease including short stature, skeletal dysplasia, facial dysmorphism, immunologic abnormalities, and Pelger-Huët anomaly. METHODS AND RESULTS: Here, we describe a 4-year-old girl who presented with dehydration in the setting of acute gastroenteritis and fever but went on to develop PALF on day 2 of hospitalization. She clinically recovered with supportive measures, but after discharge, had at least 2 additional episodes of PALF. Ultimately, she underwent liver transplant and her recurrent episodes of PALF did not recur throughout a 6-year follow-up period. Whole-exome sequencing post-liver transplant initially revealed two variants of uncertain significance in the NBAS gene. Parental studies confirmed the c.1549C > T(p.R517C; now likely pathogenic) variant from her mother and a novel c.4646T > C(p.L1549P) variant from her father. In silico analyses predicted these variants to have a deleterious effect on protein function. Consistent with previously characterized NBAS mutation-associated disease (NMAD), our patient demonstrated the following features: progeroid facial features, hypoplasia of the 12th ribs, Pelger-Huët anomaly on peripheral blood smear, and abnormal B and NK cell function. CONCLUSION: Altogether, we describe a novel pathogenic variant in the NBAS gene of a patient with NMAD and report the resolution of recurrent PALF secondary to NMAD following liver transplantation.

Role of Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Regulating Neutrophil Antifungal Activity and the Oxidative Burst During Respiratory Fungal Challenge.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that plays a critical role in regulating myeloid cell host defense. In this study, we demonstrated that GM-CSF signaling plays an essential role in antifungal defense against Aspergillus fumigatus. Mice that lack the GM-CSF receptor ß chain (GM-CSFRß) developed invasive hyphal growth and exhibited impaired survival after pulmonary challenge with A. fumigatus conidia. GM-CSFRß signaling regulated the recruitment of inflammatory monocytes to infected lungs, but not the recruitment of effector neutrophils. Cell-intrinsic GM-CSFRß signaling mediated neutrophil and inflammatory monocyte antifungal activity, because lung GM-CSFRß(-/-) leukocytes exhibited impaired conidial killing compared with GM-CSFRß(+/+) counterparts in mixed bone marrow chimeric mice. GM-CSFRß(-/-) neutrophils exhibited reduced (hydrogenated) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in vivo. Conversely, administration of recombinant GM-CSF enhanced neutrophil NADPH oxidase function, conidiacidal activity, and lung fungal clearance in A. fumigatus-challenged mice. Thus, our study illustrates the functional role of GM-CSFRß signaling on lung myeloid cell responses against inhaled A. fumigatus conidia and demonstrates a benefit for systemic GM-CSF administration.

Blood Donor Sex and Outcomes in Transfused Infants.

Red blood cell transfusion is common in neonatal intensive care. Multiple trials have evaluated different thresholds for when to administer red blood cell transfusion. In contrast, there has been less focus on studies of the characteristics of red blood cells transfused into neonates. In this review, the authors summarize the emerging literature on the potential impact of the sex of blood donors on outcomes in transfused neonates using a systematic search strategy. The authors review the uncertainty generated from studies with conflicting findings and discuss considerations regarding the impact of blood donor sex and other characteristics on neonatal outcomes.

Red Blood Cell Transfusion, Anemia, Feeding, and the Risk of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in preterm infants. Severe anemia and red blood cell (RBC) transfusion are associated with gut inflammation and injury in preclinical models and observational studies. However, there is uncertainty about the causal role of these factors in the pathogenesis of NEC. Observational studies have shown that withholding feeding during RBC transfusion may reduce the risk of NEC, although confirmatory data from randomized trials are lacking. In this review, we summarize data on feeding during RBC transfusion and its role in NEC and highlight ongoing randomized trials.

Evaluation and validation of a prediction model for extubation success in very preterm infants.

OBJECTIVE: To perform an external validation of a publicly available model predicting extubation success in very preterm infants. STUDY DESIGN: Retrospective study of infants born <1250 g at a single center. Model performance evaluated using the area under the receiver operating characteristic curve (AUROC) and comparing observed and expected probabilities of extubation success, defined as survival ≥5 d without an endotracheal tube. RESULTS: Of 177 infants, 120 (68%) were extubated successfully. The median (IQR) gestational age was 27 weeks (25-28) and weight at extubation was 915 g (755-1050). The model had acceptable discrimination (AUROC 0.72 [95% CI 0.65-0.80]) and adequate calibration (calibration slope 0.96, intercept -0.06, mean observed-to-expected difference in probability of extubation success -0.08 [95% CI -0.01, -0.15]). CONCLUSIONS: The extubation success prediction model has acceptable performance in an external cohort. Additional prospective studies are needed to determine if the model can be improved or how it can be used for clinical benefit.