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BACKGROUND: Noonan Syndrome is caused by variants in a variety of genes found in the RAS/MAPK pathway. As more causative genes for Noonan Syndrome have been identified, more phenotype variability has been found, particularly congenital heart defects. Here, we report a case of dilated coronary arteries in a pediatric patient with a RIT1 variant to add to the body of literature around this rare presentation of Noonan Syndrome. CASE PRESENTATION: A 2-month-old female was admitted due to increasing coronary artery dilation and elevated inflammatory markers. Rapid whole genome sequencing was performed and a likely pathogenic RIT1 variant was detected. This gene has been associated with a rare form of Noonan Syndrome and associated heart defects. Diagnosis of the RIT1 variant also gave reassurance about the patient's cardiac findings and allowed for more timely discharge as she was discharged to home the following day. CONCLUSIONS: This case highlights the importance of the association between dilated coronary arteries and Noonan syndrome and that careful cardiac screening should be advised in patients diagnosed with Noonan syndrome. In addition, this case emphasizes the importance of involvement of other subspecialities to determine a diagnosis. Through multidisciplinary medicine, the patient was able to return home in a timely manner with a diagnosis and the reassurance that despite her dilated coronary arteries and elevated inflammatory markers there was no immediate concern to her health.
Assuntos
Cardiopatias Congênitas , Síndrome de Noonan , Humanos , Feminino , Síndrome de Noonan/complicações , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Vasos Coronários/patologia , Proteínas ras/metabolismo , Fenótipo , MutaçãoRESUMO
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small â¼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in â¼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.
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Betacoronavirus/química , Betacoronavirus/genética , Infecções por Coronavirus/metabolismo , Bases de Dados de Proteínas , Simulação de Dinâmica Molecular , Pneumonia Viral/metabolismo , Proteoma , Sistemas de Transporte de Aminoácidos Neutros/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Enzima de Conversão de Angiotensina 2 , População Negra/genética , COVID-19 , Infecções por Coronavirus/virologia , Proteínas do Nucleocapsídeo de Coronavírus , Predisposição Genética para Doença , Variação Genética , Interações Hospedeiro-Patógeno , Humanos , Masculino , Proteínas do Nucleocapsídeo/química , Proteínas do Nucleocapsídeo/metabolismo , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Fosfoproteínas , Pneumonia Viral/virologia , Mapas de Interação de Proteínas , Processamento de Proteína Pós-Traducional , SARS-CoV-2 , Homologia de Sequência de Aminoácidos , Serina Endopeptidases/química , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Viral infections affecting the lower respiratory tract place enormous burdens on hospitals. As neither vaccines nor antiviral agents exist for many viruses, understanding risk factors and outcomes in each patient using minimally invasive analysis, such as blood, can lead to improved health care delivery. A cohort of PAXgene RNA sequencing of infants admitted with moderate or severe acute bronchiolitis and respiratory syncytial virus were compared with case-control statistical analysis and cohort-based outlier mapping for precision transcriptomics. Patients with severe bronchiolitis had signatures connected to the immune system, interferon signaling, and cytokine signaling, with marked sex differences in XIST, RPS4Y1, KDM5D, and LINC00278 for severity. Several patients had unique secondary infections, cytokine activation, immune responses, biological pathways, and immune cell activation, highlighting the need for defining patient-level transcriptomic signatures. Balancing relative contributions of cohort-based biomarker discoveries with patient's biological responses is needed to understand the totality of mechanisms of adverse outcomes in viral bronchiolitis.
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Bronquiolite Viral/virologia , Antígenos de Histocompatibilidade Menor/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Transcriptoma/efeitos dos fármacos , Bronquiolite Viral/sangue , Humanos , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/patogenicidade , Índice de Gravidade de Doença , Transcriptoma/imunologia , Viroses/tratamento farmacológico , Viroses/virologiaRESUMO
Introduction:The year 2020 was defined by the 29,903 base pairs of RNA that codes for the SARS-CoV-2 genome. SARS-CoV-2 infects humans to cause COVID-19, spreading from patient-to-patient yet impacts patients very divergently.Areas covered: Within this review, we address the known molecular mechanisms and supporting data for COVID-19 clinical course and pathology, clinical risk factors and molecular signatures, therapeutics of severe COVID-19, and reinfection/vaccination. Literature and published datasets were reviewed using PubMed, Google Scholar, and NCBI SRA tools. The combination of exaggerated cytokine signaling, pneumonia, NETosis, pyroptosis, thrombocytopathy, endotheliopathy, multiple organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS) create a positive feedback loop of severe damage in patients with COVID-19 that impacts the entire body and may persist for months following infection. Understanding the molecular pathways of severe COVID-19 opens the door for novel therapeutic design. We summarize the current insights into pathology, risk factors, secondary infections, genetics, omics, and drugs being tested to treat severe COVID-19.Expert opinion: A growing level of support suggests the need for stronger integration of biomarkers and precision medicine to guide treatment strategies of severe COVID-19, where each patient has unique outcomes and thus require guided treatment.
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COVID-19/genética , Insuficiência de Múltiplos Órgãos/genética , Síndrome do Desconforto Respiratório/genética , COVID-19/complicações , COVID-19/virologia , Citocinas/biossíntese , Citocinas/genética , Genoma Viral/genética , Humanos , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/virologia , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/virologia , SARS-CoV-2/patogenicidadeRESUMO
Rapid genome sequencing impacted real-time diagnostic and therapeutic management for patients in a nonacademic community hospital. A retrospective chart review of 24 patients identified that more than 60% had a change in medical management as a result of rapid genome sequencing.
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Tomada de Decisão Clínica/métodos , Anormalidades Congênitas/diagnóstico , Doenças Genéticas Inatas/diagnóstico , Hospitais Comunitários , Planejamento de Assistência ao Paciente , Sequenciamento Completo do Genoma/métodos , Anormalidades Congênitas/genética , Anormalidades Congênitas/terapia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Marcadores Genéticos , Acessibilidade aos Serviços de Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Michigan , Padrões de Prática Médica , Estudos Retrospectivos , Centros de Atenção Terciária , Fatores de TempoRESUMO
Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.
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Alopecia/genética , Deficiências do Desenvolvimento/genética , Transportadores de Ácidos Dicarboxílicos/genética , Megalencefalia/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/tratamento farmacológico , Alopecia/patologia , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/tratamento farmacológico , Eflornitina/uso terapêutico , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Megalencefalia/diagnóstico por imagem , Megalencefalia/tratamento farmacológico , Megalencefalia/patologia , Neuroimagem , Fenótipo , Poliaminas/metabolismo , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/patologia , Adulto JovemRESUMO
SARS-CoV-2 (COVID-19) has infected millions of people worldwide, with lethality in hundreds of thousands. The rapid publication of information, both regarding the clinical course and the viral biology, has yielded incredible knowledge of the virus. In this review, we address the insights gained for the SARS-CoV-2 proteome, which we have integrated into the Viral Integrated Structural Evolution Dynamic Database, a publicly available resource. Integrating evolutionary, structural, and interaction data with human proteins, we present how the SARS-CoV-2 proteome interacts with human disorders and risk factors ranging from cytokine storm, hyperferritinemic septic, coagulopathic, cardiac, immune, and rare disease-based genetics. The most noteworthy human genetic potential of SARS-CoV-2 is that of the nucleocapsid protein, where it is known to contribute to the inhibition of the biological process known as nonsense-mediated decay. This inhibition has the potential to not only regulate about 10% of all biological transcripts through altered ribosomal biology but also associate with viral-induced genetics, where suppressed human variants are activated to drive dominant, negative outcomes within cells. As we understand more of the dynamic and complex biological pathways that the proteome of SARS-CoV-2 utilizes for entry into cells, for replication, and for release from human cells, we can understand more risk factors for severe/lethal outcomes in patients and novel pharmaceutical interventions that may mitigate future pandemics.
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Betacoronavirus , Infecções por Coronavirus , Interações Hospedeiro-Patógeno , Pandemias , Pneumonia Viral , Proteoma , Ribossomos , COVID-19 , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Proteoma/genética , Proteoma/metabolismo , Ribossomos/genética , Ribossomos/metabolismo , Ribossomos/virologia , SARS-CoV-2 , Transcriptoma , Proteínas ViraisRESUMO
Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.
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Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Perfilação da Expressão Gênica/métodos , Pneumonia Viral/genética , Pneumonia Viral/virologia , Medicina de Precisão/métodos , COVID-19 , Humanos , Pandemias , Transcrição Gênica , Carga ViralRESUMO
OBJECTIVE: We investigated whether differences in survival exist between children of various racial/ethnic groups with cancer admitted to the PICU. DESIGN: A retrospective multicenter analysis was conducted using Virtual Pediatric Systems data from reporting centers. Demographic information, Pediatric Risk for Mortality III score, and outcome variables were analyzed using mixed-effects logistic regression modeling to assess for differences in mortality. SETTING: One hundred thirty-five PICUs in the United States. PATIENTS: Pediatric patients with cancer admitted to PICUs in the United States. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study details the analysis of 23,128 PICU admissions of 12,232 unique oncology patients representing 3% of all PICU admissions with 1,610 deaths (7.0% case fatality). African American (8.5%) and Hispanic children (8.1%) had significantly higher mortality (p < 0.05) compared with Caucasian children (6.3%). Regional analysis showed Hispanic patients to have higher mortality in the West in the United States, whereas African American patients in the South in the United States had higher mortality. A pulmonary disease diagnosis in Hispanics increased odds of mortality (odds ratio, 1.39; 95% CI, 1.13-1.70), whereas a diagnosis of shock/sepsis increased risk for mortality in African Americans (odds ratio, 1.56; 95% CI, 1.11-2.20) compared with Caucasians. There were no differences between races/ethnic groups in the rates of limitations of care. After controlling for Pediatric Risk of Mortality III, PICU length of stay, stem cell transplant status, readmissions, cancer type (solid, brain, hematologic), mechanical ventilation days, and sex, Hispanic (odds ratio, 1.24; 95% CI, 1.05-1.47) and African Americans (odds ratio, 1.37; 95% CI, 1.14-1.66) had significantly higher odds of mortality compared with Caucasians. CONCLUSIONS: The results show that after controlling for severity and cancer type, a child's race, ethnicity, and region of presentation influence mortality in the PICU. This suggests that additional investigation is warranted along with a need to rethink our approach to the evaluation and treatment of critically ill African American and Hispanic children with cancer.
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Etnicidade , Neoplasias , Criança , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Grupos Minoritários , Estudos Retrospectivos , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: Sedated intensive care patients have impaired ocular protective mechanisms putting them at risk for ocular surface disease with potential vision loss. Historically, routine eye care has been limited to critically ill patients receiving neuromuscular blockade. The aim of this project was to determine the occurrence rate of ocular surface disease in sedated and ventilated children, identify risk factors, and determine the progression of injury with routine eye care. DESIGN: Prospective cohort study. SETTING: A tertiary care medical-surgical PICU. PATIENTS: All intubated patients admitted from May 2015 to December 2016. INTERVENTIONS: Staff education regarding corneal examination with fluorescein, and routine eye care as per a PICU eye care protocol. MEASUREMENTS AND MAIN RESULTS: We evaluated 479 patients (1,242 corneal exams) and found that 15% had ocular surface disease at admission to the PICU: keratopathy 62, abrasion 16. The highest incidence was in trauma patients (39.0%) and those intubated in the emergency department (22.2%) or prehospital setting (42.9%). Of the 245 patients with multiple ocular assessments, 32.2% displayed ocular surface disease at some point during their hospitalization: keratopathy 73, abrasion 24. Ourprotocol dictated increased frequency of eye care if ocular surface disease worsened. As a result, the overall incidence of ocular surface disease decreased to 8.6% by the last examination (keratopathy 19, mild abrasion 2), but more severe ocular abnormalities such as corneal infiltrates, ulcers, or scarring were not observed. Based on multivariate analysis, clinical factors associated with increased risk of ocular surface disease included primary diagnosis, and lagophthalmos (incomplete eyelid closure). CONCLUSIONS: Ocular surface disease is an under-recognized process in critically ill pediatric patients. A standardized and dynamic protocol may improve corneal health, which in turn may reduce injury, pain, infection, and long-term vision loss.
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Cuidados Críticos , Estado Terminal , Criança , Humanos , Incidência , Lactente , Unidades de Terapia Intensiva Pediátrica , Estudos ProspectivosRESUMO
We recently described a new autosomal dominant genetic disorder in a pediatric patient caused by a heterozygous de novo mutation in the ornithine decarboxylase 1 (ODC1) gene. The new genetic disorder is characterized by global developmental delay, alopecia, overgrowth, and dysmorphic features. We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells. ODC (E.C. 4.1.1.17) is a rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spermidine, and spermine) that plays a crucial role during embryogenesis, organogenesis, and tumorigenesis. In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells. Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific 14C radioactive ODC activity assay. Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death. In conclusion, our patient and potentially other patients that carry a similar ODC1 gain-of-function mutation might benefit from treatment with DFMO, a drug with a good safety profile, to suppress the exceptionally high ODC activity and putrescine levels in the body.
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Alopecia , Derme , Deficiências do Desenvolvimento , Transportadores de Ácidos Dicarboxílicos , Fibroblastos , Mutação com Ganho de Função , Proteínas de Transporte da Membrana Mitocondrial , Alopecia/genética , Alopecia/metabolismo , Biópsia , Células Cultivadas , Pré-Escolar , Derme/metabolismo , Derme/patologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Deficiências do Desenvolvimento/patologia , Transportadores de Ácidos Dicarboxílicos/genética , Transportadores de Ácidos Dicarboxílicos/metabolismo , Eflornitina/farmacologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Putrescina/metabolismoRESUMO
Genomic sequencing has undergone massive expansion in the past 10 yr, from a rarely used research tool into an approach that has broad applications in a clinical setting. From rare disease to cancer, genomics is transforming our knowledge of biology. The transition from targeted gene sequencing, to whole exome sequencing, to whole genome sequencing has only been made possible due to rapid advancements in technologies and informatics that have plummeted the cost per base of DNA sequencing and analysis. The tools of genomics have resolved the etiology of disease for previously undiagnosable conditions, identified cancer driver gene variants, and have impacted the understanding of pathophysiology for many diseases. However, this expansion of use has also highlighted research's current voids in knowledge. The lack of precise animal models for gene-to-function association, lack of tools for analysis of genomic structural changes, skew in populations used for genetic studies, publication biases, and the "Unknown Proteome" all contribute to voids needing filled for genomics to work in a fast-paced clinical setting. The future will hold the tools to fill in these voids, with new data sets and the continual development of new technologies allowing for expansion of genomic medicine, ushering in the days to come for precision medicine. In this review we highlight these and other points in hopes of advancing and guiding precision medicine into the future for optimal success.
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Doença/genética , Sequenciamento do Exoma/métodos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Análise de Sequência de DNA/métodos , Animais , Biologia Computacional/métodos , Biologia Computacional/tendências , Previsões , Genômica/tendências , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Análise de Sequência de DNA/tendências , Sequenciamento do Exoma/tendênciasRESUMO
The ornithine decarboxylase 1 (ODC1) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, and neoplastic cell growth. Here, we report an 32-month-old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14-aa residues at the ODC protein c-terminus. This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago. Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss. We here describe for the first time a new pediatric disorder that is directly linked to a de novo pathogenic variant in the ODC1 gene. The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing. Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls. Our autosomal dominant patient who carries this gain-of-function ODC1 mutation may benefit from treatment with α-difluoromethylornithine, a well-tolerated, U.S. Food and Drug Administration (FDA). FDA-approved drug.
Assuntos
Alopecia/diagnóstico , Alopecia/genética , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Transportadores de Ácidos Dicarboxílicos/genética , Variação Genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Sequência de Aminoácidos , Sequência de Bases , Transportadores de Ácidos Dicarboxílicos/química , Transportadores de Ácidos Dicarboxílicos/metabolismo , Eritrócitos/metabolismo , Feminino , Humanos , Lactente , Proteínas de Transporte da Membrana Mitocondrial/química , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Sequenciamento do ExomaRESUMO
OBJECTIVE: To describe the state of the science, identify knowledge gaps, and offer potential future research questions regarding promising therapies for children with multiple organ dysfunction syndrome presented during the Eunice Kennedy Shriver National Institute of Child Health and Human Development Workshop on Pediatric Multiple Organ Dysfunction Syndrome (March 26-27, 2015). DATA SOURCES: Literature review, research data, and expert opinion. STUDY SELECTION: Not applicable. DATA EXTRACTION: Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities. DATA SYNTHESIS: Summary of presentations and discussion supported and supplemented by relevant literature. CONCLUSIONS: Among critically ill children, multiple organ dysfunction syndrome is relatively common and associated with significant morbidity and mortality. For outcomes to improve, effective therapies aimed at preventing and treating this condition must be discovered and rigorously evaluated. In this article, a number of potential opportunities to enhance current care are highlighted including the need for a better understanding of the pharmacokinetics and pharmacodynamics of medications, the effect of early and optimized nutrition, and the impact of effective glucose control in the setting of multiple organ dysfunction syndrome. Additionally, a handful of the promising therapies either currently being implemented or developed are described. These include extracorporeal therapies, anticytokine therapies, antitoxin treatments, antioxidant approaches, and multiple forms of exogenous steroids. For the field to advance, promising therapies and other therapies must be assessed in rigorous manner and implemented accordingly.
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Cuidados Críticos/métodos , Insuficiência de Múltiplos Órgãos/terapia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Antitoxinas/uso terapêutico , Criança , Terapia Combinada , Circulação Extracorpórea , Humanos , Hipoglicemiantes/uso terapêutico , Terapia Nutricional/métodos , Pediatria , Esteroides/uso terapêutico , Resultado do TratamentoAssuntos
Anticorpos Monoclonais Humanizados/efeitos dos fármacos , Tratamento Farmacológico da COVID-19 , Diabetes Mellitus/tratamento farmacológico , Hipertensão/tratamento farmacológico , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Biomarcadores/análise , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/mortalidade , Comorbidade , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/imunologia , Diabetes Mellitus/mortalidade , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/imunologia , Hipertensão/mortalidade , Contagem de Leucócitos , Linfócitos/imunologia , Linfócitos/virologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/virologia , Prognóstico , Fatores de Risco , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Circulating progenitor cells have been extensively studied in the context of heart disease in adults. In these patients, they have been demonstrated to be markers of myocardial injury and recovery as well as potential therapeutic agents. However, studies in children are much more limited. Here we review current knowledge pertaining to circulating progenitor cells in the context of childhood cardiovascular disease. Priorities for further research are also highlighted.
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Doenças Cardiovasculares/fisiopatologia , Células-Tronco/citologia , Ponte Cardiopulmonar , Criança , Cardiopatias Congênitas/fisiopatologia , Humanos , Proteínas de Membrana/análiseRESUMO
OBJECTIVES: Secondary hemophagocytic lymphohistiocytosis, macrophage activating syndrome, and sepsis share the same inflammatory phenotype leading often to multiple organ dysfunction syndrome needing intensive care. The goal of this article is to describe our experience with anakinra (Kineret), a recombinant interleukin-1 receptor antagonist, in decreasing the systemic inflammation. DESIGN: Retrospective case series. SETTING: The PICU at the Helen DeVos Children's Hospital (Grand Rapids, MI). PATIENTS: The records of eight critically ill children presumed to have secondary hemophagocytic lymphohistiocytosis at our institution between January 1, 2011, and July 31, 2012, were reviewed. INTERVENTIONS: All of the patients were treated with anakinra (Kineret) and in some cases systemic corticosteroids as first-line therapy for secondary hemophagocytic lymphohistiocytosis. MEASUREMENTS AND MAIN RESULTS: Patients had a median age of 14 years and a median Pediatric Risk of Mortality score of 11.5. Four were previously healthy and four had underlying diseases that could have made them susceptible to secondary hemophagocytic lymphohistiocytosis. Indications for PICU transfer were respiratory distress 50% (4 of 8), cardiovascular instability 37.5% (3 of 8), and chest pain (1 of 8). Five of the patients (62.5%) were mechanically ventilated and 62.5% (5 of 8) received vasoactive infusions. Inflammatory markers were assessed linearly at the start of therapy and 7 days later. Baseline C-reactive protein was 206 ± 50 mg/L (mean ± SEM) at the start of anakinra and decreased by 67.1% to 68 ± 36 mg/L (p = 0.03). Ferritin decreased by 63.8% to 3,210 ± 1,178 ng/mL (p = 0.30), and fibrinogen decreased by 42% to 158 ± 41 mg/dL (p = 0.03). Absolute neutrophil count (p = 0.38) and absolute lymphocyte count (p = 0.69) did not change significantly. No infections were attributed to anakinra therapy. One patient died long after treatment with anakinra while receiving pre-hematopoietic stem cell transplant chemotherapy. CONCLUSIONS: Anakinra could represent a promising therapeutic approach in these life-threatening disorders that are likely underdiagnosed and often difficult to treat.
Assuntos
Antirreumáticos/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Adolescente , Anti-Inflamatórios/uso terapêutico , Proteína C-Reativa/metabolismo , Criança , Cuidados Críticos , Feminino , Ferritinas/sangue , Fibrinogênio/metabolismo , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Contagem de Linfócitos , Linfócitos , Linfo-Histiocitose Hemofagocítica/sangue , Síndrome de Ativação Macrofágica/tratamento farmacológico , Masculino , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Neutrófilos , Estudos Retrospectivos , Sepse/tratamento farmacológico , Esteroides/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: To describe packed RBC utilization patterns in trauma patients admitted to a PICU and study associated outcomes while controlling for severity. DESIGN: Retrospective cohort study. SETTING: The PICU of a tertiary care children's hospital. PATIENTS: All pediatric trauma patients admitted to Helen DeVos Children's Hospital PICU between June 2007 and July 2010, either directly from the emergency department or transferred from another institution. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 389 trauma patients, 107 patients (27.5%) transferred to the PICU were transfused with blood products. Of these transfusions, 81 were packed RBC transfusions and 26 were other blood products. Only 73 of the packed RBC transfusions had a documented time of transfusion: 17 (23.3%) were transfused prior to PICU admission, seven (9.5%) both before and after PICU, and 49 (67.1%) only after PICU admission. After adjusting for injury severity score, transfused patients had higher odds of needing mechanical ventilation (odds ratios, 9.2; 95% CI, 3.6-23.3) and higher risk of mortality (odds ratios, 8.6; 95% CI, 2.6-28.6), when compared with nontransfused patients. Mean age of packed RBC was 19.6 ± 9.3 days (mean ± SD). The impact of age of packed RBCs on mortality was examined as a categorical variable at 14, 21, and 28 days. Packed RBCs more than 28 days old (14/61 patients) were associated with longer lengths of stay (13 ± 12 vs 7 ± 6; p < 0.03), lower discharge Glasgow Coma Scale score (9 ± 6 vs 13 ± 4; p< 0.03), and more mortality (43% vs 13%; p < 0.02) when compared with blood less than 28 days old. CONCLUSIONS: In pediatric trauma patients, transfusion of packed RBC and use of older RBC units are associated with higher risk of adverse outcomes independent of injury severity.
Assuntos
Cuidados Críticos , Transfusão de Eritrócitos , Ferimentos e Lesões/terapia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Escala de Gravidade do Ferimento , Tempo de Internação , Masculino , Respiração Artificial , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the cost and safety of placement of Broviac catheters in children by pediatric intensivists in a sedation suite versus placement by pediatric surgeons in the operating room. DESIGN: Single-center retrospective analysis. SETTING: Pediatric sedation suite and operating rooms in a tertiary care children's hospital. PATIENTS: All pediatric patients with Broviac catheters placed (n = 253) at this institution over a 3-year period from 2007 to 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We reviewed the charts of all pediatric patients with Broviac catheters placed, either by intensivists or surgeons, and compared cost and outcomes. Procedure safety was assessed and categorized into immediate, short-term (within 2 wk of procedure), and long-term outcomes. Anesthetic safety and billing data for the procedure were also collected. Among similar patient populations, immediate complications, such as pneumothorax, procedure failure (p > 0.999), and anesthetic complications (p = 0.60), were not significantly different. Short-term outcomes, including infection (p = 0.27) and catheter malfunction (p > 0.999), were not different. Long-term outcomes, including mean indwelling catheter days (p = 0.60) and removal due to catheter infection (p = 0.09), were not different between the groups. Overall cost of the procedure was significantly different: $7,031 (± $784) when performed by surgeons and $3,565 (± $311) when performed by intensivists (p < 0.001). CONCLUSIONS: Pediatric critical care physicians can place Broviac catheters as safely as pediatric surgeons and at a lower cost in a defined patient population.