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1.
BMJ Open ; 14(4): e078137, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38670610

RESUMEN

OBJECTIVES: In trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of trial findings. Swissped-RECOVERY was set up as one of the first randomised controlled trials worldwide, investigating the comparative effectiveness of anti-inflammatory treatment with intravenous methylprednisolone or intravenous immunoglobulins in children and adolescents with Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We present one approach towards improving the interpretation of non-randomised treatment in a randomised controlled trial. DESIGN: This is a pre-planned ancillary analysis of the Swissped-RECOVERY trial, a randomised multicentre open-label two-arm trial. SETTING: 10 Swiss paediatric hospitals (secondary and tertiary care) participated. PARTICIPANTS: Paediatric patients hospitalised with PIMS-TS. INTERVENTIONS: All patient-first intercurrent events, if applicable, were presented to an independent adjudication committee consisting of four international paediatric COVID-19 experts to provide independent clinical adjudication to a set of standardised questions relating to whether additional non-randomised treatments were clinically indicated and disease classification at the time of the intercurrent event. RESULTS: Of 41 treatments in 75 participants (24/41 (59%) and 17/41 (41%) in the intravenous methylprednisolone and immunoglobulin arms of the trial, respectively), two-thirds were considered indicated. The most common treatment (oral glucocorticoids, 14/41, 35%) was mostly considered not indicated (11/14, 79%), although in line with local guidelines. Intercurrent events among patients with Shock-like PIMS-TS at baseline were mostly considered indicated. A significant proportion of patients with undifferentiated PIMS-TS at baseline were not attributed to the same group at the time of the intercurrent event (6/12 unchanged, 4/12 Kawasaki disease-like, 2/12 Shock-like). CONCLUSION: The masked adjudication of intercurrent events contributes to the interpretation of results in open-label trials and should be incorporated in the future. TRIAL REGISTRATION NUMBERS: SNCTP000004720 and NCT04826588.


Asunto(s)
COVID-19/complicaciones , Inmunoglobulinas Intravenosas , Metilprednisolona , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , Metilprednisolona/uso terapéutico , Metilprednisolona/administración & dosificación , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Niño , Suiza , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Adolescente , Hospitales Pediátricos , Tratamiento Farmacológico de COVID-19 , Femenino , Masculino , Antiinflamatorios/uso terapéutico , Preescolar , Resultado del Tratamiento
2.
medRxiv ; 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38496479

RESUMEN

Inflammatory syndromes, including those caused by infection, are a major cause of hospital admissions among children and are often misdiagnosed because of a lack of advanced molecular diagnostic tools. In this study, we explored the utility of circulating cell-free RNA (cfRNA) in plasma as an analyte for the differential diagnosis and characterization of pediatric inflammatory syndromes. We profiled cfRNA in 370 plasma samples from pediatric patients with a range of inflammatory conditions, including Kawasaki disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), viral infections and bacterial infections. We developed machine learning models based on these cfRNA profiles, which effectively differentiated KD from MIS-C - two conditions presenting with overlapping symptoms - with high performance (Test Area Under the Curve (AUC) = 0.97). We further extended this methodology into a multiclass machine learning framework that achieved 81% accuracy in distinguishing among KD, MIS-C, viral, and bacterial infections. We further demonstrated that cfRNA profiles can be used to quantify injury to specific tissues and organs, including the liver, heart, endothelium, nervous system, and the upper respiratory tract. Overall, this study identified cfRNA as a versatile analyte for the differential diagnosis and characterization of a wide range of pediatric inflammatory syndromes.

4.
J Intensive Care Med ; : 8850666241233189, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38414438

RESUMEN

Background: Multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 varies widely in its presentation and severity, with low mortality in high-income countries. In this study in 16 Latin American countries, we sought to characterize patients with MIS-C in the pediatric intensive care unit (PICU) compared with those hospitalized on the general wards and analyze the factors associated with severity, outcomes, and treatment received. Study Design: An observational ambispective cohort study was conducted including children 1 month to 18 years old in 84 hospitals from the REKAMLATINA network from January 2020 to June 2022. Results: A total of 1239 children with MIS-C were included. The median age was 6.5 years (IQR 2.5-10.1). Eighty-four percent (1043/1239) were previously healthy. Forty-eight percent (590/1239) were admitted to the PICU. These patients had more myocardial dysfunction (20% vs 4%; P < 0.01) with no difference in the frequency of coronary abnormalities (P = 0.77) when compared to general ward subjects. Of the children in the PICU, 83.4% (494/589) required vasoactive drugs, and 43.4% (256/589) invasive mechanical ventilation, due to respiratory failure and pneumonia (57% vs 32%; P = 0.01). On multivariate analysis, the factors associated with the need for PICU transfer were age over 6 years (aOR 1.76 95% CI 1.25-2.49), shock (aOR 7.06 95% CI 5.14-9.80), seizures (aOR 2.44 95% CI 1.14-5.36), thrombocytopenia (aOR 2.43 95% CI 1.77-3.34), elevated C-reactive protein (aOR 1.89 95% CI 1.29-2.79), and chest x-ray abnormalities (aOR 2.29 95% CI 1.67-3.13). The overall mortality was 4.8%. Conclusions: Children with MIS-C who have the highest risk of being admitted to a PICU in Latin American countries are those over age six, with shock, seizures, a more robust inflammatory response, and chest x-ray abnormalities. The mortality rate is five times greater when compared with high-income countries, despite a high proportion of patients receiving adequate treatment.

5.
Pediatr Res ; 95(3): 692-697, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36797460

RESUMEN

BACKGROUND: About 10-20% of Kawasaki disease (KD) patients are resistant to the initial infusion of intravenous immunoglobin (IVIG). The aim of this study was to assess whether IVIG resistance in KD patients could be predicted using standard clinical and laboratory features. METHODS: Data were from two cohorts: a Korean cohort of 7101 KD patients from 2015 to 2017 and a cohort of 649 KD patients from San Diego enrolled from 1998 to 2021. Features included laboratory values, the worst Z-score from the initial echocardiogram or during hospitalization, and the five clinical KD signs at presentation. RESULTS: Five machine learning models achieved a maximum median AUC of 0.711 [IQR: 0.706-0.72] in the Korean cohort and 0.696 [IQR: 0.609-0.722] in the San Diego cohort during stratified 10-fold cross-validation using significant laboratory features identified from univariate analysis. Adding the Z-score, KD clinical signs, or both did not considerably improve the median AUC in either cohort. CONCLUSIONS: Using commonly measured clinical laboratory data alone or in conjunction with echocardiographic findings and clinical features is not sufficient to predict IVIG resistance. Further attempts to predict IVIG resistance will need to incorporate additional data such as transcriptomics, proteomics, and genetics to achieve meaningful predictive utility. IMPACT: We demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD). Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner. Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful.


Asunto(s)
Inmunoglobulinas Intravenosas , Síndrome Mucocutáneo Linfonodular , Humanos , Lactante , Biomarcadores , Resistencia a Medicamentos , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Estudios Retrospectivos , Pueblos del Este de Asia
6.
World J Pediatr ; 20(2): 143-152, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38133726

RESUMEN

BACKGROUND: Recent infection with SARS­CoV­2 in children has been associated with multisystem inflammatory syndrome in children (MIS-C). SARS­CoV­2 has undergone different mutations. Few publications exist about specific variants and their correlation with the severity of MIS-C. METHODS: This was a single-center, retrospective study including all patients admitted with MIS-C at Rady Children's Hospital-San Diego between May 2020 and March 2022. Local epidemiologic data, including viral genomic information, were obtained from public records. Demographics, clinical presentation, laboratory values, and outcomes were obtained from electronic medical records. RESULTS: The analysis included 104 pediatric patients. Four MIS-C waves were identified. Circulating variants in San Diego during the first wave included clades 20A to C. During the second wave, there were variants from clades 20A to C, 20G, 21C (Epsilon), 20I (Alpha), and 20J (Gamma). The third wave had Delta strains (clades 21A, 21I, and 21J), and the fourth had Omicron variants (clades 21K, 21L, and 22C). MIS-C presented with similar symptoms and laboratory findings across all waves. More patients were admitted to the pediatric intensive care unit (PICU) (74%) and required inotropic support (63%) during the second wave. None of the patients required mechanical circulatory support, and only two required invasive ventilatory support. There was no mortality. CONCLUSIONS: The various strains of SARS-CoV-2 triggered MIS-C with differing severities, with the second wave having a more severe clinical course. Whether the differences in disease severity across variants were due to changes in the virus or other factors remains unknown.


Asunto(s)
COVID-19/complicaciones , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica , Humanos , Niño , SARS-CoV-2/genética , Estudios Retrospectivos , Progresión de la Enfermedad
7.
J Biopharm Stat ; : 1-19, 2023 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-38095587

RESUMEN

Multisystem Inflammatory Syndrome in children (MIS-C) is a rare and novel pediatric complication linked to COVID-19 exposure, which was first identified in April 2020. A small n, Sequential, Multiple Assignment, Randomized Trial (snSMART) was applied to the Multisystem Inflammatory Syndrome Therapies in Children Comparative Effectiveness Study (MISTIC) to efficiently evaluate multiple competing treatments. In the MISTIC snSMART study, participants are randomized to one of three interventions (steroids, infliximab or anakinra), and potentially re-randomized to the remaining two treatments depending on their response to the first randomized treatment. However, given the novelty and urgency of the MIS-C disease, in addition to patient welfare concerns, treatments were not always administered sequentially, but allowed to be administered concurrently if deemed medically necessary. We propose a pragmatic modification to the original snSMART design to address the analysis of concurrent versus sequential treatments in the MISTIC study. A modified Bayesian joint stage model is developed that can distinguish a concurrent treatment effect from a sequential treatment effect. A simulation study is conducted to demonstrate the improved accuracy and efficiency of the primary aim to estimate the first stage treatments' response rates and the secondary aim to estimate the combined first and second stage treatments' responses in the proposed model compared to the standard snSMART Bayesian joint stage model. We observed that the modified model has improved efficiency in terms of bias and rMSE under large sample size settings.

8.
JACC Case Rep ; 26: 102077, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-38094174

RESUMEN

The hypercoagulable state in Kawasaki disease (KD) may lead to complex cardiovascular sequelae. We present the case of a 2-month-old infant with complete KD complicated by giant coronary artery aneurysms, coronary sinus thrombosis, and post-myocardial infarction syndrome (Dressler syndrome), resulting in 2 distinct episodes of pericardial effusion. (Level of Difficulty: Intermediate.).

9.
Artículo en Inglés | MEDLINE | ID: mdl-38083437

RESUMEN

Kawasaki disease (KD) is a leading cause of acquired heart disease in children and is characterized by the presence of a combination of five clinical signs assessed during the physical examination. Timely treatment of intravenous immunoglobin is needed to prevent coronary artery aneurysm formation, but KD is usually diagnosed when pediatric patients are evaluated by a clinician in the emergency department days after onset. One or more of the five clinical signs usually manifests in pediatric patients prior to ED admission, presenting an opportunity for earlier intervention if families receive guidance to seek medical care as soon as clinical signs are observed along with a fever for at least five days. We present a deep learning framework for a novel screening tool to calculate the relative risk of KD by analyzing images of the five clinical signs. The framework consists of convolutional neural networks to separately calculate the risk for each clinical sign, and a new algorithm to determine what clinical sign is in an image. We achieved a mean accuracy of 90% during 10-fold cross-validation and 88% during external validation for the new algorithm. These results demonstrate the algorithms in the proposed screening tool can be utilized by families to determine if their child should be evaluated by a clinician based on the number of clinical signs consistent with KD.Clinical Relevance- This screening framework has the potential for earlier clinical evaluation and detection of KD to reduce the risk of coronary artery complications.


Asunto(s)
Aprendizaje Profundo , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/diagnóstico por imagen , Fiebre , Vasos Coronarios
10.
JAMA Netw Open ; 6(11): e2343801, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-37948083

RESUMEN

This case series examines outcomes among patients with giant coronary artery aneurysms after Kawasaki disease treated with direct oral anticoagulants (DOACs).


Asunto(s)
Aneurisma Coronario , Síndrome Mucocutáneo Linfonodular , Humanos , Vasos Coronarios , Síndrome Mucocutáneo Linfonodular/complicaciones , Aneurisma Coronario/diagnóstico por imagen , Aneurisma Coronario/etiología , Inmunoglobulinas Intravenosas , Pacientes
11.
Med ; 4(9): 635-654.e5, 2023 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-37597512

RESUMEN

BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.


Asunto(s)
Benchmarking , Investigación Biomédica , Niño , Humanos , Diagnóstico Diferencial , Motivos de Nucleótidos , Fiebre/diagnóstico , Fiebre/genética , ARN
12.
Lancet Child Adolesc Health ; 7(10): 697-707, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37598693

RESUMEN

BACKGROUND: Although Kawasaki disease is commonly regarded as a single disease entity, variability in clinical manifestations and disease outcome has been recognised. We aimed to use a data-driven approach to identify clinical subgroups. METHODS: We analysed clinical data from patients with Kawasaki disease diagnosed at Rady Children's Hospital (San Diego, CA, USA) between Jan 1, 2002, and June 30, 2022. Patients were grouped by hierarchical clustering on principal components with k-means parcellation based on 14 variables, including age at onset, ten laboratory test results, day of illness at the first intravenous immunoglobulin infusion, and normalised echocardiographic measures of coronary artery diameters at diagnosis. We also analysed the seasonality and Kawasaki disease incidence from 2002 to 2019 by subgroup. To explore the biological underpinnings of identified subgroups, we did differential abundance analysis on proteomic data of 6481 proteins from 32 patients with Kawasaki disease and 24 healthy children, using linear regression models that controlled for age and sex. FINDINGS: Among 1016 patients with complete data in the final analysis, four subgroups were identified with distinct clinical features: (1) hepatobiliary involvement with elevated alanine transaminase, gamma-glutamyl transferase, and total bilirubin levels, lowest coronary artery aneurysm but highest intravenous immunoglobulin resistance rates (n=157); (2) highest band neutrophil count and Kawasaki disease shock rate (n=231); (3) cervical lymphadenopathy with high markers of inflammation (erythrocyte sedimentation rate, C-reactive protein, white blood cell, and platelet counts) and lowest age-adjusted haemoglobin Z scores (n=315); and (4) young age at onset with highest coronary artery aneurysm but lowest intravenous immunoglobulin resistance rates (n=313). The subgroups had distinct seasonal and incidence trajectories. In addition, the subgroups shared 211 differential abundance proteins while many proteins were unique to a subgroup. INTERPRETATION: Our data-driven analysis provides insight into the heterogeneity of Kawasaki disease, and supports the existence of distinct subgroups with important implications for clinical management and research design and interpretation. FUNDING: US National Institutes of Health and the Irving and Francine Suknow Foundation.


Asunto(s)
Aneurisma , Síndrome Mucocutáneo Linfonodular , Estados Unidos , Humanos , Niño , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/epidemiología , Inmunoglobulinas Intravenosas/uso terapéutico , Proteómica , Análisis por Conglomerados , Aneurisma/tratamiento farmacológico
13.
Int J Mol Sci ; 24(15)2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37569694

RESUMEN

Although Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) share some clinical manifestations, their cardiovascular outcomes are different, and this may be reflected at the level of the endothelial cell (EC). We performed RNA-seq on cultured ECs incubated with pre-treatment sera from KD (n = 5), MIS-C (n = 7), and healthy controls (n = 3). We conducted a weighted gene co-expression network analysis (WGCNA) using 935 transcripts differentially expressed between MIS-C and KD using relaxed filtering (unadjusted p < 0.05, >1.1-fold difference). We found seven gene modules in MIS-C, annotated as an increased TNFα/NFκB pathway, decreased EC homeostasis, anti-inflammation and immune response, translation, and glucocorticoid responsive genes and endothelial-mesenchymal transition (EndoMT). To further understand the difference in the EC response between MIS-C and KD, stringent filtering was applied to identify 41 differentially expressed genes (DEGs) between MIS-C and KD (adjusted p < 0.05, >2-fold-difference). Again, in MIS-C, NFκB pathway genes, including nine pro-survival genes, were upregulated. The expression levels were higher in the genes influencing autophagy (UBD, EBI3, and SQSTM1). Other DEGs also supported the finding by WGCNA. Compared to KD, ECs in MIS-C had increased pro-survival transcripts but reduced transcripts related to EndoMT and EC homeostasis. These differences in the EC response may influence the different cardiovascular outcomes in these two diseases.


Asunto(s)
COVID-19 , Enfermedades del Tejido Conjuntivo , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Síndrome Mucocutáneo Linfonodular/genética , Células Endoteliales , Síndrome de Respuesta Inflamatoria Sistémica/genética
14.
JAMA Netw Open ; 6(5): e2314291, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-37200028

RESUMEN

Importance: Cardiac dysfunction and myocarditis have emerged as serious complications of multisystem inflammatory syndrome in children (MIS-C) and vaccines against SARS-CoV-2. Understanding the role of autoantibodies in these conditions is essential for guiding MIS-C management and vaccination strategies in children. Objective: To investigate the presence of anticardiac autoantibodies in MIS-C or COVID-19 vaccine-induced myocarditis. Design, Setting, and Participants: This diagnostic study included children with acute MIS-C or acute vaccine myocarditis, adults with myocarditis or inflammatory cardiomyopathy, healthy children prior to the COVID-19 pandemic, and healthy COVID-19 vaccinated adults. Participants were recruited into research studies in the US, United Kingdom, and Austria starting January 2021. Immunoglobulin G (IgG), IgM, and IgA anticardiac autoantibodies were identified with immunofluorescence staining of left ventricular myocardial tissue from 2 human donors treated with sera from patients and controls. Secondary antibodies were fluorescein isothiocyanate-conjugated antihuman IgG, IgM, and IgA. Images were taken for detection of specific IgG, IgM, and IgA deposits and measurement of fluorescein isothiocyanate fluorescence intensity. Data were analyzed through March 10, 2023. Main Outcomes and Measures: IgG, IgM and IgA antibody binding to cardiac tissue. Results: By cohort, there were a total of 10 children with MIS-C (median [IQR] age, 10 [13-14] years; 6 male), 10 with vaccine myocarditis (median age, 15 [14-16] years; 10 male), 8 adults with myocarditis or inflammatory cardiomyopathy (median age, 55 [46-63] years; 6 male), 10 healthy pediatric controls (median age, 8 [13-14] years; 5 male), and 10 healthy vaccinated adults (all older than 21 years, 5 male). No antibody binding above background was observed in human cardiac tissue treated with sera from pediatric patients with MIS-C or vaccine myocarditis. One of the 8 adult patients with myocarditis or cardiomyopathy had positive IgG staining with raised fluorescence intensity (median [IQR] intensity, 11 060 [10 223-11 858] AU). There were no significant differences in median fluorescence intensity in all other patient cohorts compared with controls for IgG (MIS-C, 6033 [5834-6756] AU; vaccine myocarditis, 6392 [5710-6836] AU; adult myocarditis or inflammatory cardiomyopathy, 5688 [5277-5990] AU; healthy pediatric controls, 6235 [5924-6708] AU; healthy vaccinated adults, 7000 [6423-7739] AU), IgM (MIS-C, 3354 [3110-4043] AU; vaccine myocarditis, 3843 [3288-4748] AU; healthy pediatric controls, 3436 [3313-4237] AU; healthy vaccinated adults, 3543 [2997-4607] AU) and IgA (MIS-C, 3559 [2788-4466] AU; vaccine myocarditis, 4389 [2393-4780] AU; healthy pediatric controls, 3436 [2425-4077] AU; healthy vaccinated adults, 4561 [3164-6309] AU). Conclusions and Relevance: This etiological diagnostic study found no evidence of antibodies from MIS-C and COVID-19 vaccine myocarditis serum binding cardiac tissue, suggesting that the cardiac pathology in both conditions is unlikely to be driven by direct anticardiac antibody-mediated mechanisms.


Asunto(s)
COVID-19 , Miocarditis , Adulto , Humanos , Masculino , Niño , Adolescente , Persona de Mediana Edad , Miocarditis/etiología , Vacunas contra la COVID-19/efectos adversos , Autoanticuerpos , COVID-19/prevención & control , Pandemias , SARS-CoV-2 , Vacunación , Inmunoglobulina G , Inmunoglobulina A , Fluoresceínas , Inmunoglobulina M
15.
J Pediatric Infect Dis Soc ; 12(6): 322-331, 2023 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-37255317

RESUMEN

BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.


Asunto(s)
COVID-19 , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , COVID-19/diagnóstico , COVID-19/genética , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/genética , Hospitales , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/genética , Prueba de COVID-19
16.
Arch Dis Child ; 108(10): 833-838, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37258054

RESUMEN

OBJECTIVE: Children with Kawasaki disease (KD) and an initial echocardiogram that demonstrates coronary artery aneurysms (CAAs, Z score ≥2.5) are at high risk for severe cardiovascular complications. We sought to determine if primary adjunctive infliximab treatment at a dose of either 5 or 10 mg/kg, compared with intravenous immunoglobulin (IVIG) alone, is associated with a greater likelihood of CAA regression in patients with KD with CAA at the time of diagnosis. DESIGN AND SETTING: Single-centre observational study. PATIENTS: Children with acute KD and Z score ≥2.5 at baseline. INTERVENTIONS: Primary adjunctive infliximab (5 or 10 mg/kg) within 48 hours of initiating IVIG 2 g/kg. MAIN OUTCOME MEASURES: Incidence of CAA regression to Zmax <2 within 2 months of disease onset. RESULTS: Of the 168 patients with KD, 111 received IVIG alone and 57 received primary adjunctive infliximab therapy: 39 received 5 mg/kg and 18 received 10 mg/kg. Incidence of CAA regression to Zmax <2 within 2 months was statistically significant at 52%, 62% and 83% in the IVIG alone, IVIG+infliximab 5 mg/kg and IVIG+infliximab 10 mg/kg, respectively. The multivariable logistic regression model adjusting for age, sex, baseline Zmax and bilateral CAA at baseline showed that IVIG plus 10 mg/kg infliximab was significantly associated with a greater likelihood of CAA regression (adjusted OR: 4.45, 95% CI 1.17 to 16.89, p=0.028) compared with IVIG alone. The difference between IVIG+infliximab 5 mg/kg and IVIG alone was not significant. CONCLUSIONS: Primary adjunctive high-dose 10 mg/kg infliximab treatment was associated with a greater likelihood of CAA regression in patients with CAA at the time of diagnosis.


Asunto(s)
Aneurisma Coronario , Enfermedad de la Arteria Coronaria , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Lactante , Síndrome Mucocutáneo Linfonodular/complicaciones , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Infliximab/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Vasos Coronarios , Aneurisma Coronario/tratamiento farmacológico , Aneurisma Coronario/etiología , Aneurisma Coronario/diagnóstico , Estudios Retrospectivos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/etiología
17.
Lancet Rheumatol ; 5(4): e184-e199, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36855438

RESUMEN

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health.

18.
J Pediatr ; 263: 113346, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-36775190

RESUMEN

OBJECTIVES: To describe the clinical presentation, management, and outcomes of Kawasaki disease (KD) in Latin America and to evaluate early prognostic indicators of coronary artery aneurysm (CAA). STUDY DESIGN: An observational KD registry-based study was conducted in 64 participating pediatric centers across 19 Latin American countries retrospectively between January 1, 2009, and December 31, 2013, and prospectively from June 1, 2014, to May 31, 2017. Demographic and initial clinical and laboratory data were collected. Logistic regression incorporating clinical factors and maximum coronary artery z-score at initial presentation (between 10 days before and 5 days after intravenous immunoglobulin [IVIG]) was used to develop a prognostic model for CAA during follow-up (>5 days after IVIG). RESULTS: Of 1853 patients with KD, delayed admission (>10 days after fever onset) occurred in 16%, 25% had incomplete KD, and 11% were resistant to IVIG. Among 671 subjects with reported coronary artery z-score during follow-up (median: 79 days; IQR: 36, 186), 21% had CAA, including 4% with giant aneurysms. A simple prognostic model utilizing only a maximum coronary artery z-score ≥2.5 at initial presentation was optimal to predict CAA during follow-up (area under the curve: 0.84; 95% CI: 0.80, 0.88). CONCLUSION: From our Latin American population, coronary artery z-score ≥2.5 at initial presentation was the most important prognostic factor preceding CAA during follow-up. These results highlight the importance of early echocardiography during the initial presentation of KD.


Asunto(s)
Aneurisma Coronario , Síndrome Mucocutáneo Linfonodular , Niño , Humanos , Aneurisma Coronario/epidemiología , Aneurisma Coronario/etiología , Aneurisma Coronario/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , América Latina/epidemiología , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/epidemiología , Estudios Retrospectivos
19.
Contemp Clin Trials Commun ; 32: 101060, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36694613

RESUMEN

Background: Multisystem Inflammatory Syndrome in Children (MIS-C), which occurs 2-6 weeks after initial exposure to SARS-CoV-2, was first identified in early 2020 when patients presented with fever and significant inflammation, often requiring management in the intensive care unit. To date, there has been no clinical trial to determine the most effective treatment. This study compares anti-inflammatory treatments that were selected based on current treatments for Kawasaki disease, a coronary artery vasculitis that shares many clinical features with MIS-C. Methods: This randomized, comparative effectiveness trial of children with MIS-C uses the small N Sequential Multiple Assignment Randomized Trial (snSMART) design for rare diseases to compare multiple therapies within an individual. Study participants were treated first with intravenous immunoglobulin (IVIG), and if needed, subjects were then randomized to one of three additional treatments (steroids, anakinra, or infliximab). Participants were re-randomized to remaining treatments if they did not demonstrate clinical improvement. Conclusion: This trial continues to enroll eligible participants to determine the most effective therapies in addition to IVIG and best order in which to use them to treat MIS-C. Trial Registration: NCT04898231.

20.
Pediatr Blood Cancer ; 70(2): e30059, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36385736

RESUMEN

We sought to examine cardiovascular toxicities associated with tyrosine kinase inhibitors in pediatrics. We examined 1624 pediatric adverse events with imatinib, dasatinib, sorafenib, pazopanib, crizotinib, and ruxolitinib reported to the Food and Drug Administration between January 1, 2015, and August 14, 2020. There were 102 cardiovascular event reports. Hypertension was the most commonly reported cardiovascular event and was most frequently associated with sorafenib and pazopanib. The presence of infection increased the reporting odds of cardiovascular events overall and specifically cardiac arrest, heart failure, and hypertension. These data provide early insight into cardiovascular toxicities with tyrosine kinase inhibitor use in pediatrics.


Asunto(s)
Antineoplásicos , Insuficiencia Cardíaca , Hipertensión , Estados Unidos , Humanos , Niño , Sorafenib/efectos adversos , United States Food and Drug Administration , Inhibidores de Proteínas Quinasas/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Antineoplásicos/efectos adversos
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