Search

Purpose Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. Methods We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN’s Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. Results More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12–7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06–64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin $$\ge 500$$ ≥ 500 ng/mL, OR: 2.16, 95% CI: 1.28–3.66, p = 0.004), lymphopenia (lymphocyte count p = 0.027), thrombocytopenia (platelet count p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10–2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21–14.5, p = 0.019). Conclusion Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

OBJECTIVE: To provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection. METHODS: A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting. RESULTS: The ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available.

We hypothesized that serum biomarkers of inflammation including chemokine, cytokine, pituitary hormones, and growth factors following cardiac arrest in children would independently associate with 6-month neurologic outcome.In this prospective observational single center study of children with in-hospital and out-of-hospital cardiac arrest surviving to intensive care unit admission, serum was obtained twice per 24 h period between 0 h and 96 h and once at approximately 196 h post-cardiac arrest. Inflammatory mediators, hormones, and growth factors were analyzed by Luminex Multiplex Bead Immunoassay. We recorded demographics, resuscitation characteristics, and Pediatric Cerebral Performance Category (PCPC) at 6 months. We analyzed the association and area under the curve (AUC) of biomarker levels with favorable (PCPC 1-3) or unfavorable (PCPC 4-6, or 1 increase from baseline) outcome.Forty-two children (50% female; median age of 2.5 [IQR: 0.4-10.2]) were enrolled and 18 (42%) died prior to 6-month follow up. Receiver operator curves for initial levels of ciliary neurotrophic factor (CNTF, AUC 0.84, 95% CI 0.73-0.96, p 0.001) and interleukin (IL-17, AUC 0.84, 95% CI 0.73-0.97, p 0.001) best classified favorable versus unfavorable 6-month outcome. In multivariable analysis, initial levels of CNTF and IL-17 remained associated with 6-month PCPC. Peak levels of interferon-γ-inducible protein 10 (IP-10), CNTF, and hepatocyte growth factor (HGF) were also independently associated with outcome.Increased serum concentrations of CNTF and IL-17 associated with unfavorable 6-month neurologic outcome of children surviving cardiac arrest. Further investigation of the prognostic utility and roles of CNTF and IL-17 in the pathophysiology of post-cardiac arrest syndrome are warranted. This project is registered with clinicaltrials.gov (NCT00797680) as "Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest: A Randomized, Controlled Trial".

OBJECTIVE: Hemophagocytic lymphohistiocytosis (HLH) poses significant challenges due to limited tools to guide clinical decisions in a population at high risk of death. We sought to assess whether disseminated intravascular coagulation (DIC) and hepatobiliary dysfunction (HBD), significant comorbidities seen in critical care settings, would identify HLH patients with increased risk of mortality. DESIGN: Retrospective chart review. SETTING: Single-center pediatric intensive care unit PATIENTS: All patients admitted to a tertiary care children’s hospital diagnosed with HLH from 2005 – 2012 INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Forty-three patients were diagnosed with HLH with median age of 61 months. The 5-year overall survival was 51% (22/43). Univariate analyses revealed ferritin levels > 10,000 (ng/mL), international normalized ratio >1.5, or platelet counts < 100,000/mcL at initiation of dexamethasone were individually associated with mortality. Development of DIC, HBD or both increased the likelihood of death in HLH patients (relative risk; 95% confidence interval) (6; 1.4 – 34; p

Post-hoc subgroup analysis of the negative trial of interleukin-1β receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030.7 ηg/ml, ±SEM 7,411.1). In total 11 rare (minor allele frequency

Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an ‘innocent bystander’ biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.

OBJECTIVES: Genetic disorders are a leading contributor to mortality in the neonatal and pediatric intensive care unit (ICU) in the United States. Although individually rare, there are over 6200 single gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing (rWGS) is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN: Retrospective cohort study SETTING: Single-center PICU in a tertiary children’s hospital PATIENTS: Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS: rWGS with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS: A molecular diagnosis was made by rWGS in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS: This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rWGS in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rWGS early in PICU admission when the underlying etiology is unclear.

To evaluate the relationship between detection of DNA viruses, ferritin, and outcomes in children with severe sepsis.We enrolled 75 pediatric patients with severe sepsis admitted to a tertiary care children's hospital. Plasma ferritin was measured within 48 hours of diagnosis and subsequently twice weekly. Herpes simplex type 1, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and adenovirus DNAemia were assessed by polymerase chain reaction.The incidence of DNAemia was increased significantly in patients with ferritin ≥1000 ng/mL (78% vs 28%; P .05). Patients with ferritin ≥1000 ng/mL were more likely to have multiple DNA viruses detected in plasma (39% vs 4%; P .001). The number of viruses detected in plasma directly correlated with the degree of hyperferritinemia and development of combined hepatobiliary and hematologic dysfunction after we controlled for bacterial and fungal coinfections (P .05) as well as increased mortality after we controlled for severity of illness and cancer diagnosis (OR 2.6, 95% CI 1.1-6.3, P.05).Viral DNAemia was associated with hyperferritinemia and adverse outcome in pediatric severe sepsis. Prospective studies are needed to determine whether hyperferritinemia may be used to identify patients at risk of occult DNAemia.

The overall incidence of acute kidney injury (AKI) in the USA is estimated to be about 7/1000 population [1]. Older adults and children are disproportionately affected in a bimodal distribution mirroring the incidence of sepsis [2], the leading cause of AKI [3–6]. Even mild forms of AKI are associated with increased risk of hospital mortality [6, 7], and AKI may result in chronic kidney disease and life-long morbidity, shortened survival and increased costs [8]. Moreover, severity of AKI varies by etiology and sepsis-associated AKI tends to be most severe. For example, KDIGO stage 3 occurs in 20% of patients with septic shock [9]. Once acquired, the consequences of AKI are also unequally distributed. Approximately one third of patients exhibit no reversal of renal dysfunction within the first few days of AKI. Roughly 25% will never recover, and experience a fivefold increase in mortality over the ensuing year [10]. Even among patients with sepsis-associated AKI, outcomes are heterogeneous and different mechanisms may be involved [11]—indeed, no fewer than six have been proposed [12]. Renal endothelial pathology is prevalent in experimental models of sepsis [12, 13]. Endothelial injury can reduce microcirculatory flow leading to perfusion abnormalities and interstitial infiltration of inflammatory cells [13]. However, the reasons some patients exhibit these pathologic features while others do not are obscure.