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High ferritin is an important and sensitive biomarker for hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system where serum ferritin > 1000ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This single-center, real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.
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Current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here we performed a case-control study to test and possibly improve these clinical criteria. We also developed two complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (n=366) were children <16 years with verified familial and/or genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (n=25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329+361 children in two cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on the number of diagnostic criteria fulfilled from 17 variables studied, reveled almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without NK-cell function was also studied which showed accuracy 99.0% (sensitivity 96.2%; specificity 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.
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BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.
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Hiperferritinemia , Síndrome de Ativação Macrofágica , Sepse , Humanos , Criança , Síndrome de Ativação Macrofágica/complicações , Sepse/complicações , Citocinas , FerritinasRESUMO
Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection. It remains unclear how MIS-C phenotypes vary across SARS-CoV-2 variants. We aimed to investigate clinical characteristics and outcomes of MIS-C across SARS-CoV-2 eras. Methods: We performed a multicentre observational retrospective study including seven paediatric hospitals in four countries (France, Spain, U.K., and U.S.). All consecutive confirmed patients with MIS-C hospitalised between February 1st, 2020, and May 31st, 2022, were included. Electronic Health Records (EHR) data were used to calculate pooled risk differences (RD) and effect sizes (ES) at site level, using Alpha as reference. Meta-analysis was used to pool data across sites. Findings: Of 598 patients with MIS-C (61% male, 39% female; mean age 9.7 years [SD 4.5]), 383 (64%) were admitted in the Alpha era, 111 (19%) in the Delta era, and 104 (17%) in the Omicron era. Compared with patients admitted in the Alpha era, those admitted in the Delta era were younger (ES -1.18 years [95% CI -2.05, -0.32]), had fewer respiratory symptoms (RD -0.15 [95% CI -0.33, -0.04]), less frequent non-cardiogenic shock or systemic inflammatory response syndrome (SIRS) (RD -0.35 [95% CI -0.64, -0.07]), lower lymphocyte count (ES -0.16 × 109/uL [95% CI -0.30, -0.01]), lower C-reactive protein (ES -28.5 mg/L [95% CI -46.3, -10.7]), and lower troponin (ES -0.14 ng/mL [95% CI -0.26, -0.03]). Patients admitted in the Omicron versus Alpha eras were younger (ES -1.6 years [95% CI -2.5, -0.8]), had less frequent SIRS (RD -0.18 [95% CI -0.30, -0.05]), lower lymphocyte count (ES -0.39 × 109/uL [95% CI -0.52, -0.25]), lower troponin (ES -0.16 ng/mL [95% CI -0.30, -0.01]) and less frequently received anticoagulation therapy (RD -0.19 [95% CI -0.37, -0.04]). Length of hospitalization was shorter in the Delta versus Alpha eras (-1.3 days [95% CI -2.3, -0.4]). Interpretation: Our study suggested that MIS-C clinical phenotypes varied across SARS-CoV-2 eras, with patients in Delta and Omicron eras being younger and less sick. EHR data can be effectively leveraged to identify rare complications of pandemic diseases and their variation over time. Funding: None.
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OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
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Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Médicos , Adulto , Criança , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/terapia , Consenso , Comitês ConsultivosRESUMO
OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
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Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Reumatologia , Criança , Adulto , Humanos , Estados Unidos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/etiologia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/terapia , ConsensoRESUMO
OBJECTIVES: Acute disorders of consciousness (DoC) in pediatric severe sepsis are associated with increased risk of morbidity and mortality. We sought to examine the frequency of and factors associated with DoC in children with sepsis-induced organ failure. DESIGN: Secondary analysis of the multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study (PHENOMS). SETTING: Nine tertiary care PICUs in the United States. PATIENTS: Children less than 18 years old admitted to a PICU with severe sepsis and at least one organ failure during a PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was frequency of DoC, defined as Glasgow Coma Scale (GCS) less than 12 in the absence of sedatives during an ICU stay, among children with severe sepsis and the following: single organ failure, nonphenotypeable multiple organ failure (MOF), MOF with one of the PHENOMS phenotypes (immunoparalysis-associated MOF [IPMOF], sequential liver failure-associated MOF, thrombocytopenia-associated MOF), or MOF with multiple phenotypes. A multivariable logistic regression analysis was performed to evaluate the association between clinical variables and organ failure groups with DoC. Of 401 children studied, 71 (18%) presented with DoC. Children presenting with DoC were older (median 8 vs 5 yr; p = 0.023), had increased hospital mortality (21% vs 10%; p = 0.011), and more frequently presented with both any MOF (93% vs 71%; p < 0.001) and macrophage activation syndrome (14% vs 4%; p = 0.004). Among children with any MOF, those presenting with DoC most frequently had nonphenotypeable MOF and IPMOF (52% and 34%, respectively). In the multivariable analysis, older age (odds ratio, 1.07; 95% CI, 1.01-1.12) and any MOF (3.22 [1.19-8.70]) were associated with DoC. CONCLUSIONS: One of every five children with severe sepsis and organ failure experienced acute DoC during their PICU stay. Preliminary findings suggest the need for prospective evaluation of DoC in children with sepsis and MOF.
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Falência Hepática , Sepse , Criança , Humanos , Lactente , Adolescente , Insuficiência de Múltiplos Órgãos/etiologia , Transtornos da Consciência/complicações , Unidades de Terapia Intensiva Pediátrica , Doença Aguda , Sepse/complicaçõesRESUMO
Sepsis contributes to 1 of every 5 deaths globally with 3 million per year occurring in children. To improve clinical outcomes in pediatric sepsis, it is critical to avoid "one-size-fits-all" approaches and to employ a precision medicine approach. To advance a precision medicine approach to pediatric sepsis treatments, this review provides a summary of two phenotyping strategies, empiric and machine-learning-based phenotyping based on multifaceted data underlying the complex pediatric sepsis pathobiology. Although empiric and machine-learning-based phenotypes help clinicians accelerate the diagnosis and treatments, neither empiric nor machine-learning-based phenotypes fully encapsulate all aspects of pediatric sepsis heterogeneity. To facilitate accurate delineations of pediatric sepsis phenotypes for precision medicine approach, methodological steps and challenges are further highlighted.
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Pediatric encephalitis has significant morbidity and mortality, yet 50% of cases are unexplained. Host genetics plays a role in encephalitis' development; however, the contributing variants are poorly understood. One child with anti-NMDA receptor encephalitis and ten with unexplained encephalitis underwent whole genome sequencing to identify rare candidate variants in genes known to cause monogenic immunologic and neurologic disorders, and polymorphisms associated with increased disease risk. Using the professional Human Genetic Mutation Database (Qiagen), we divided the candidate variants into three categories: monogenic deleterious or potentially deleterious variants (1) in a disease-consistent inheritance pattern; (2) in carrier states; and (3) disease-related polymorphisms. Six patients (55%) had a deleterious or potentially deleterious variant in a disease-consistent inheritance pattern, five (45%) were heterozygous carriers for an autosomal recessive condition, and six (55%) carried a disease-related polymorphism. Finally, seven (64%) had more than one variant, suggesting possible polygenetic risk. Among variants identified were those implicated in atypical hemolytic uremic syndrome, common variable immunodeficiency, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. This preliminary study shows genetic variation related to inborn errors of immunity in acute pediatric encephalitis. Future research is needed to determine if these variants play a functional role in the development of unexplained encephalitis.
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Encefalite , Linfo-Histiocitose Hemofagocítica , Humanos , Criança , Mutação , Heterozigoto , Polimorfismo Genético , Encefalite/genética , Variação GenéticaRESUMO
OBJECTIVES: Interest in using bedside C-reactive protein (CRP) and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies has piqued with the COVID-19 pandemic experience. Our first objective was to identify patterns in CRP and ferritin trajectory among critically ill pediatric sepsis patients. We then examined the association between these different groups of patients in their inflammatory cytokine responses, systemic inflammation, and mortality risks. DATA SOURCES: A prospective, observational cohort study. STUDY SELECTION: Children with sepsis and organ failure in nine pediatric intensive care units in the United States. DATA EXTRACTION: Two hundred and fifty-five children were enrolled. Five distinct clinical multi-trajectory groups were identified. Plasma CRP (mg/dL), ferritin (ng/mL), and 31 cytokine levels were measured at two timepoints during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin. DATA SYNTHESIS: Group 1 had normal CRP and ferritin levels ( n = 8; 0% mortality); Group 2 had high CRP levels that became normal, with normal ferritin levels throughout ( n = 80; 5% mortality); Group 3 had high ferritin levels alone ( n = 16; 6% mortality); Group 4 had very high CRP levels, and high ferritin levels ( n = 121; 11% mortality); and Group 5 had very high CRP and very high ferritin levels ( n = 30; 40% mortality). Cytokine responses differed across the five groups, with ferritin levels correlated with macrophage inflammatory protein 1α levels and CRP levels reflective of many cytokines. CONCLUSIONS: Bedside CRP and ferritin levels can be used together to distinguish groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks. These data suggest future potential value in personalized clinical trials with specific targets for anti-inflammatory therapies.
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COVID-19 , Sepse , Criança , Humanos , Proteína C-Reativa/metabolismo , Estudos Prospectivos , Pandemias , Biomarcadores , Ferritinas , Inflamação , Citocinas/metabolismoRESUMO
BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.
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Síndrome de Ativação Macrofágica , Sepse , Trombocitopenia , Anti-Inflamatórios , Proteína C-Reativa , Criança , Ensaios Clínicos como Assunto , Creatinina , Ferritinas , Humanos , Aprendizado de Máquina , Síndrome de Ativação Macrofágica/complicações , Insuficiência de Múltiplos Órgãos/etiologia , Escores de Disfunção Orgânica , Fenótipo , Reprodutibilidade dos TestesRESUMO
Sepsis is a heterogenous and imprecise syndrome that includes multiple phenotypes, some of which are amenable to specific therapies. Developing new therapies for sepsis will require focusing on subsets of patients. Key to improving care is evaluating patients for sepsis mimics and treatable diseases whose manifestations lead to a clinical classification of sepsis. Because sepsis is common, it is easy to overlook unusual causes of organ failure and succumb to confirmation bias about the nature of an illness. Careful attention to medical and family histories, focused diagnostic testing, and subspecialty input can help identify potentially treatable diseases masquerading as typical sepsis.
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Sepse , Humanos , Sepse/diagnóstico , Sepse/terapiaRESUMO
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 SARS-CoV-2 infection. Recommendations are also provided for children with hyperinflammation during COVID-19, the acute, infectious phase of SARS-CoV-2 infection. METHODS: The Task Force is composed of 9 pediatric rheumatologists and 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 anonymous voting and webinar discussion. 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). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. RESULTS: The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS-C and recommendations for initial immunomodulatory treatment of MIS-C. CONCLUSION: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.
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COVID-19 , Reumatologia , Adulto , COVID-19/complicações , Criança , Humanos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/terapia , Estados UnidosRESUMO
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 [Formula: see text] ng/mL, OR: 2.16, 95% CI: 1.28-3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 - 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12-2.76, 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.
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Síndromes de Imunodeficiência , Sepse , Criança , Humanos , Síndromes de Imunodeficiência/genética , Fenótipo , Prevalência , Sepse/epidemiologia , Sepse/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Learning the causal structure helps identify risk factors, disease mechanisms, and candidate therapeutics for complex diseases. However, although complex biological systems are characterized by nonlinear associations, existing bioinformatic methods of causal inference cannot identify the nonlinear relationships and estimate their effect size. RESULTS: To overcome these limitations, we developed the first computational method that explicitly learns nonlinear causal relations and estimates the effect size using a deep neural network approach coupled with the knockoff framework, named causal directed acyclic graphs using deep learning variable selection (DAG-deepVASE). Using simulation data of diverse scenarios and identifying known and novel causal relations in molecular and clinical data of various diseases, we demonstrated that DAG-deepVASE consistently outperforms existing methods in identifying true and known causal relations. In the analyses, we also illustrate how identifying nonlinear causal relations and estimating their effect size help understand the complex disease pathobiology, which is not possible using other methods. CONCLUSIONS: With these advantages, the application of DAG-deepVASE can help identify driver genes and therapeutic agents in biomedical studies and clinical trials.
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Redes Neurais de Computação , Simulação por Computador , CausalidadeRESUMO
AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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".