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1.
Ann Rheum Dis ; 82(10): 1271-1285, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37487610

RESUMO

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.


Assuntos
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 , Consenso
2.
Crit Care ; 27(1): 347, 2023 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-37674218

RESUMO

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.


Assuntos
Hiperferritinemia , Síndrome de Ativação Macrofágica , Sepse , Humanos , Criança , Síndrome de Ativação Macrofágica/complicações , Sepse/complicações , Citocinas , Ferritinas
3.
Pediatr Crit Care Med ; 24(10): 840-848, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37314247

RESUMO

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.


Assuntos
Falência Hepática , Sepse , Criança , Humanos , Lactente , Adolescente , Insuficiência de Múltiplos Órgãos/etiologia , Transtornos da Consciência/complicações , Unidades de Terapia Intensiva Pediátrica , Doença Aguda , Sepse/complicações
4.
Genes Immun ; 23(7): 235-239, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36198812

RESUMO

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.


Assuntos
Encefalite , Linfo-Histiocitose Hemofagocítica , Humanos , Criança , Mutação , Heterozigoto , Polimorfismo Genético , Encefalite/genética , Variação Genética
5.
J Clin Immunol ; 42(2): 350-364, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34973142

RESUMO

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.


Assuntos
Síndromes de Imunodeficiência , Sepse , Criança , Humanos , Síndromes de Imunodeficiência/genética , Fenótipo , Prevalência , Sepse/epidemiologia , Sepse/genética , Sequenciamento do Exoma
6.
Crit Care ; 26(1): 128, 2022 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-35526000

RESUMO

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.


Assuntos
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 Testes
7.
Pediatr Crit Care Med ; 23(12): 968-979, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36178701

RESUMO

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.


Assuntos
COVID-19 , Sepse , Criança , Humanos , Proteína C-Reativa/metabolismo , Estudos Prospectivos , Pandemias , Biomarcadores , Ferritinas , Inflamação , Citocinas/metabolismo
8.
Genes Immun ; 20(6): 520-526, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29977033

RESUMO

Post-hoc subgroup analysis of the negative trial of interleukin-1ß 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 <5%) pathogenic or likely pathogenic variants causal for the monogenic disorders of Familial Hemophagocytic Lymphohistiocytosis, atypical Hemolytic Uremic Syndrome, Familial Mediterranean Fever, and Cryopyrin-associated Periodic Fever were identified. In these conditions, seven of the identified variants are currently targeted with IL1RA and four with anti-C5 antibody. Gene-targeted precision medicine may benefit this subgroup of patients with septic shock and pathogenic immune variation.


Assuntos
Ferritinas/sangue , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/mortalidade , Choque Séptico/genética , Choque Séptico/mortalidade , Adulto , Idoso , Síndromes Periódicas Associadas à Criopirina/genética , Febre Familiar do Mediterrâneo/genética , Feminino , Síndrome Hemolítico-Urêmica/genética , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Síndrome de Ativação Macrofágica/tratamento farmacológico , Síndrome de Ativação Macrofágica/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologia , Sequenciamento do Exoma
9.
J Pediatr ; 213: 82-87.e2, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31303335

RESUMO

OBJECTIVE: To evaluate the relationship between detection of DNA viruses, ferritin, and outcomes in children with severe sepsis. STUDY DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.


Assuntos
DNA Viral/sangue , Ferritinas/sangue , Sepse/sangue , Sepse/virologia , Viremia/sangue , Viremia/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Masculino , Sensibilidade e Especificidade , Sepse/mortalidade , Taxa de Sobrevida , Viremia/mortalidade
10.
Pediatr Crit Care Med ; 25(6): e311-e312, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38836717
11.
Int Immunol ; 29(9): 401-409, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28541437

RESUMO

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.


Assuntos
Catarata/congênito , Ferritinas/metabolismo , Hemocromatose , Inflamação , Distúrbios do Metabolismo do Ferro/congênito , Ferro/metabolismo , Reação de Fase Aguda , Animais , Humanos , Imunidade Inata , Imunomodulação
12.
Genome Res ; 24(6): 930-41, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24671852

RESUMO

What is the significance of the extensive variability observed in individual members of a single-cell phenotype? This question is particularly relevant to the highly differentiated organization of the brain. In this study, for the first time, we analyze the in vivo variability within a neuronal phenotype in terms of input type. We developed a large-scale gene-expression data set from several hundred single brainstem neurons selected on the basis of their specific synaptic input types. The results show a surprising organizational structure in which neuronal variability aligned with input type along a continuum of sub-phenotypes and corresponding gene regulatory modules. Correlations between these regulatory modules and specific cellular states were stratified by synaptic input type. Moreover, we found that the phenotype gradient and correlated regulatory modules were maintained across subjects. As these specific cellular states are a function of the inputs received, the stability of these states represents "attractor"-like states along a dynamic landscape that is influenced and shaped by inputs, enabling distinct state-dependent functional responses. We interpret the phenotype gradient as arising from analog tuning of underlying regulatory networks driven by distinct inputs to individual cells. Our results change the way we understand how a phenotypic population supports robust biological function by integrating the environmental experience of individual cells. Our results provide an explanation of the functional significance of the pervasive variability observed within a cell type and are broadly applicable to understanding the relationship between cellular input history and cell phenotype within all tissues.


Assuntos
Redes Reguladoras de Genes , Variação Genética , Neurônios/metabolismo , Fenótipo , Transmissão Sináptica , Animais , Modelos Genéticos , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Núcleo Solitário/citologia , Transcrição Gênica , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
16.
Front Pediatr ; 11: 1035576, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36793336

RESUMO

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.

17.
Arthritis Rheumatol ; 75(10): 1714-1732, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37486733

RESUMO

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.


Assuntos
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 Consultivos
18.
EClinicalMedicine ; 64: 102212, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37745025

RESUMO

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.

19.
Crit Care Clin ; 38(2): 195-211, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35369943

RESUMO

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.


Assuntos
Sepse , Humanos , Sepse/diagnóstico , Sepse/terapia
20.
Gigascience ; 122022 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-37395630

RESUMO

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.


Assuntos
Redes Neurais de Computação , Simulação por Computador , Causalidade
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