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1.
J Nepal Health Res Counc ; 18(4): 789-791, 2021 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-33510530

RESUMEN

Multisystem inflammatory syndrome in children is a new childhood inflammatory disorder associated with respiratory syndrome coronavirus 2 (SARS-CoV-2). This illness of elevated inflammatory markers and multiple organ involvement similar to Kawasaki disease is not commonly reported from Asia. A 17-month-old boy presented with acute onset fever, rash, non-exudative conjunctivitis and swellings of hands and legs. In x-ray chest there was infiltration on the right lower lobe and echocardiography showed evidence of coronary arteritis. The diagnosis of multisystem inflammatory syndrome in children was confirmed on the basis of characteristic clinical features and laboratory parameters fulfilling standard case definition for multisystem inflammatory syndrome in children. The child responded to treatment with intravenous immunoglobulin and high dose aspirin. Hence, amidst SARS-CoV-2 pandemic, multisystem inflammatory syndrome in children should be suspected and effectively treated even in a country like Nepal. Keywords: Kawasaki disease; multiple inflammatory syndrome in children; Nepal; respiratory syndrome coronavirus 2.


Asunto(s)
/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Aspirina/uso terapéutico , /patología , Humanos , Inmunoglobulinas/uso terapéutico , Lactante , Masculino , Nepal , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/patología
2.
Clin Med (Lond) ; 21(1): e96-e99, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33479086

RESUMEN

The emergence of SARS-CoV-2 has proven to be a challenge to healthcare bodies globally. The virus has been associated with a spectrum of clinical features, from anosmia to gastrointestinal upset to multiorgan dysfunction in the most severe cases. Given the range of features observed, it is important to be aware that infectious diseases can present atypically. Furthermore, in many hospitals, including our own, teenagers aged 16 to 18 years old are admitted under the care of adult medical services. Clinicians should be aware of patients presenting with the novel condition of paediatric inflammatory multisystem disorder - temporarily associated with SARS-CoV-2 (PIMS-TS).


Asunto(s)
/diagnóstico , Inmunoglobulinas Intravenosas/uso terapéutico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Adolescente , /epidemiología , Hospitalización , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Tomografía Computarizada por Rayos X
4.
J Biol Regul Homeost Agents ; 34(5): 1633-1636, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33023287

RESUMEN

COVID-19 derives from infection with Coronavirus [severe acute respiratory syndrome (SARS)-CoV-2] and is associated with high morbidity and mortality due to release of a storm of pro-inflammatory cytokines and thrombogenic agents resulting in destruction of the lungs. Many reports indicate that a considerable number of patients who are positive for SARS-CoV-2 are asymptomatic or have mild symptoms. However, increasing evidence suggests that many such patients who either recovered from or had mild symptoms after COVID-19 exhibit diffuse, multiorgan, symptoms months after the infection. These symptoms include malaise, myalgias, chest tightness, brain fog and other neuropsychiatric symptoms that were originally reported in children and named Multisystem Inflammatory Syndrome (MIS-C). Now the US Center for Disease Control (CDC) announced the recognition of a similar condition in adults, named Multisystem Inflammatory Syndrome (MIS-A). The symptoms characterizing these conditions are very similar to those associated with Mast Cell Activation Syndrome (MCAS, US ICD-110 code D89.42-idiopathic mast cell activation syndrome). Hence, the possibility of MCAS should be evaluated in any patient with MIS and/or multisystem inflammatory symptoms. In either case, these syndromes should be addressed with liposomal formulation (in olive pomace oil) of the flavone luteolin (e.g. PureLut® or FibroProtek®) together with the antihistamine rupatadine, which also has anti-platelet activating factor (PAF) activity and inhibits mast cells that have been implicated in the pathogenesis of cytokine storms in COVID-19.


Asunto(s)
Infecciones por Coronavirus/patología , Mastocitosis/virología , Neumonía Viral/patología , Síndrome de Respuesta Inflamatoria Sistémica , Adulto , Betacoronavirus , Niño , Ciproheptadina/administración & dosificación , Ciproheptadina/análogos & derivados , Humanos , Luteolina/administración & dosificación , Mastocitosis/tratamiento farmacológico , Pandemias , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico
5.
Crit Care Resusc ; 22(3): 227-236, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32900329

RESUMEN

OBJECTIVE: The systemic inflammatory response syndrome (SIRS) is a dysregulated response that contributes to critical illness. Adjunctive acetylsalicylic acid (ASA) treatment may offer beneficial effects by increasing the synthesis of specialised proresolving mediators (a subset of polyunsaturated fatty acid-derived lipid mediators). DESIGN: Pilot, feasibility, multicentre, double-blind, randomised, placebo-controlled trial. SETTING: Four interdisciplinary intensive care units (ICUs) in Australia. PARTICIPANTS: Critically ill patients with SIRS. INTERVENTIONS: ASA 100 mg 12-hourly or placebo, administered within 24 hours of ICU admission and continued until ICU day 7, discharge or death, whichever came first. MAIN OUTCOME MEASURES: Interleukin-6 (IL-6) serum concentration at 48 hours after randomisation and, in a prespecified subgroup of patients, serum lipid mediator concentrations measured by mass spectrometry. RESULTS: The trial was discontinued in December 2017 due to slow recruitment and after the inclusion of 48 patients. Compared with placebo, ASA did not decrease IL-6 serum concentration at 48 hours. In the 32 patients with analysis of lipid mediators, low-dose ASA increased the concentration of 15-hydroxyeicosatetraenoic acid, a proresolving precursor of lipoxin A4, and reduced the concentration of the proinflammatory cytochrome P-dependent mediators 17-HETE (hydroxyeicosatetraenoic acid), 18-HETE and 20-HETE. In the eicosapentaenoic acid pathway, ASA significantly increased the concentration of the anti-inflammatory mediators 17,18-DiHETE (dihydroxyeicosatetraenoic acid) and 14,15-DiHETE. CONCLUSIONS: In ICU patients with SIRS, low-dose ASA did not significantly alter serum IL-6 concentrations, but it did affect plasma concentrations of certain lipid mediators. The ability to measure lipid mediators in clinical samples and to monitor the effect of ASA on their levels unlocks a potential area of biological investigation in critical care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN 12614001165673).


Asunto(s)
Aspirina/administración & dosificación , Enfermedad Crítica , Citocinas/efectos de los fármacos , Metaboloma/efectos de los fármacos , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Australia , Método Doble Ciego , Estudios de Factibilidad , Humanos , Interleucina-6/sangre , Lípidos , Resultado del Tratamiento
6.
BMC Infect Dis ; 20(1): 716, 2020 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-32993540

RESUMEN

BACKGROUND: A healthy 25-year-old woman developed COVID-19 disease with clinical characteristics resembling Multisystem Inflammatory Syndrome in Children (MIS-C), a rare form of COVID-19 described primarily in children under 21 years of age. CASE PRESENTATION: The patient presented with 1 week of weakness, dyspnea, and low-grade fevers, followed by mild cough, sore throat, vomiting, diarrhea, and lymph node swelling. She was otherwise healthy, with no prior medical history. Her hospital course was notable for profound acute kidney injury, leukocytosis, hypotension, and cardiac dysfunction requiring ICU admission and vasopressor support. MIS-C-like illness secondary to COVID-19 was suspected due to physical exam findings of conjunctivitis, mucositis, and shock. She improved following IVIG, aspirin, and supportive care, and was discharged on hospital day 5. CONCLUSION: MIS-C-like illness should be considered in adults presenting with atypical clinical findings and concern for COVID-19. Further research is needed to support the role of IVIG and aspirin in this patient population.


Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Síndrome de Respuesta Inflamatoria Sistémica/complicaciones , Adulto , Aspirina/administración & dosificación , Aspirina/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Tos/complicaciones , Diarrea/complicaciones , Disnea/complicaciones , Femenino , Fiebre/complicaciones , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/uso terapéutico , Pandemias , Faringitis/complicaciones , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Reacción en Cadena de la Polimerasa , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/virología , Resultado del Tratamiento , Vómitos/complicaciones
7.
J Pediatric Infect Dis Soc ; 9(5): 622-625, 2020 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-32951037

RESUMEN

The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, we treated 2 patients with defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved during treatment. Moreover, coagulation parameters indicating hypofibrinolysis and complement activation normalized. The pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 infection is a severe complication of coronavirus disease 2019. Since impaired coagulation and thrombosis/endotheliitis are suspected pathomechanisms, 2 patients received defibrotide, a profibrinolytic, antithrombotic, antiinflammatory oligonucleotide. Symptoms resolved and hypofibrinolysis/complement activation normalized during treatment.


Asunto(s)
Infecciones por Coronavirus/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Neumonía Viral/complicaciones , Polidesoxirribonucleótidos/uso terapéutico , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Dolor Abdominal/etiología , Adolescente , Betacoronavirus , Factores de Coagulación Sanguínea/análisis , Niño , Infecciones por Coronavirus/diagnóstico , Femenino , Fiebre/etiología , Humanos , Pandemias , Neumonía Viral/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Linfocitos T/inmunología
8.
Br J Hosp Med (Lond) ; 81(8): 1-10, 2020 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-32845750

RESUMEN

The COVID-19 pandemic has predominantly affected the adult population. The disease is less well-defined in children (≤18 years). This review summarises the current understanding of the epidemiology, clinical manifestations, and management of COVID-19 in children and adolescents. The prevalence of COVID-19 is significantly lower in children than adults, but paediatric disease is likely underdiagnosed as a result of the high numbers of asymptomatic or mild cases. Children are vulnerable to family cluster outbreaks, but are unlikely to be index cases within a household. Vertical transmission or breast milk transmission are yet to be proven. Between 10 and 90% of paediatric COVID-19 cases are asymptomatic. Symptomatic cases typically present with mild symptoms, including cough, fever and sore throat. Intensive care admission and mortality are rare. Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 is a rare, but severe, newly emerging phenotype. At present, there is no specific treatment for COVID-19 in adults or children; management is usually supportive. For severe or critical disease, including paediatric multisystem inflammatory syndrome temporally associated with COVID-19, the decision to start antiviral or immunomodulatory therapy should be on a case-by-case basis; in the UK, this should be done within a clinical trial. Further research is needed into both the disease course and treatment of paediatric COVID-19.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Adolescente , Corticoesteroides/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus , Niño , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Oxigenación por Membrana Extracorpórea , Hemofiltración , Humanos , Unidades de Cuidado Intensivo Pediátrico/estadística & datos numéricos , Mortalidad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Reacción en Cadena en Tiempo Real de la Polimerasa , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología
9.
Pediatr Emerg Care ; 36(10): 500-504, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32826642

RESUMEN

In late March and early April, New York City was an epicenter of the COVID-19 pandemic. Citizens were ordered to stay at home to flatten the curve. The adult population was affected with a severe respiratory illness as well as acute kidney injury, cardiomyopathy, arrhythmia, and thromboembolism. Although children were not affected in the same manner, weeks after the peak, reports from other countries emerged about cases of pediatric patients presenting with a novel inflammatory syndrome. We present 4 patients along with their emergency department course, so providers will have a better understanding of the identification and workup of these patients. Currently, it is unclear when this inflammatory syndrome develops in respect to a COVID-19 infection. The clinical features of this syndrome seem to overlap between Kawasaki disease, toxic shock syndrome, and myocarditis. All patients presenting to our emergency department had fever, variable rash, abdominal pain, vomiting, and/or diarrhea. Patients remained persistently tachycardic and febrile despite being given proper doses of antipyretics. Severity of presentations varied among the 4 cases. All 4 patients were found to have antibodies to COVID-19. All patients required admission, but 2 required the pediatric intensive care unit for cardiac and/or respiratory support or closer monitoring. Upon follow-up on our patients, it seems that most patients are recovering with treatment, and overall, there is a low reported mortality rate.


Asunto(s)
Infecciones por Coronavirus/diagnóstico , Pandemias , Neumonía Viral/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Adolescente , Antiinflamatorios/uso terapéutico , Betacoronavirus , Niño , Preescolar , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Servicio de Urgencia en Hospital , Femenino , Fiebre/epidemiología , Hospitalización , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Unidades de Cuidado Intensivo Pediátrico , Masculino , Ciudad de Nueva York , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Respiración Artificial , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Resultado del Tratamiento
10.
Lancet Infect Dis ; 20(11): e276-e288, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32818434

RESUMEN

As severe acute respiratory syndrome coronavirus 2 continues to spread worldwide, there have been increasing reports from Europe, North America, Asia, and Latin America describing children and adolescents with COVID-19-associated multisystem inflammatory conditions. However, the association between multisystem inflammatory syndrome in children and COVID-19 is still unknown. We review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19. We also discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in paediatric patients who are severely ill. These insights provide evidence for the need to develop a clear case definition and treatment protocol for this new condition and also shed light on future therapeutic interventions and the potential for vaccine development. TRANSLATIONS: For the French, Chinese, Arabic, Spanish and Russian translations of the abstract see Supplementary Materials section.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Adolescente , Antiinflamatorios no Esteroideos/uso terapéutico , Antivirales/uso terapéutico , Niño , Preescolar , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Lactante , Recién Nacido , Masculino , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/inmunología , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Factores de Riesgo , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/virología , Adulto Joven
11.
J Clin Invest ; 130(11): 5942-5950, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-32701511

RESUMEN

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.


Asunto(s)
Corticoesteroides/administración & dosificación , Betacoronavirus/metabolismo , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunomodulación , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Síndrome de Respuesta Inflamatoria Sistémica , Adolescente , Biomarcadores/sangre , Niño , Preescolar , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Lactante , Interleucina-10/sangre , Interleucina-6/sangre , Síndrome de Activación Macrofágica/sangre , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/tratamiento farmacológico , Síndrome de Activación Macrofágica/inmunología , Masculino , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/inmunología , Péptido Natriurético Encefálico/sangre , Estudios Retrospectivos , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/inmunología
12.
Sci Adv ; 6(23): eaaz5466, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32548259

RESUMEN

Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Endotoxemia/tratamiento farmacológico , Nanopartículas/química , Escualeno/química , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Adenosina/administración & dosificación , Adenosina/química , Animales , Antioxidantes/administración & dosificación , Antioxidantes/química , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Modelos Animales de Enfermedad , Endotoxemia/inducido químicamente , Femenino , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/química , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/patología , Neumonía Viral/virología , Escualeno/administración & dosificación , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Resultado del Tratamiento , alfa-Tocoferol/administración & dosificación , alfa-Tocoferol/química
13.
BMJ ; 369: m2094, 2020 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-32493739

RESUMEN

OBJECTIVES: To describe the characteristics of children and adolescents affected by an outbreak of Kawasaki-like multisystem inflammatory syndrome and to evaluate a potential temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN: Prospective observational study. SETTING: General paediatric department of a university hospital in Paris, France. PARTICIPANTS: 21 children and adolescents (aged ≤18 years) with features of Kawasaki disease who were admitted to hospital between 27 April and 11 May 2020 and followed up until discharge by 15 May 2020. MAIN OUTCOME MEASURES: The primary outcomes were clinical and biological data, imaging and echocardiographic findings, treatment, and outcomes. Nasopharyngeal swabs were prospectively tested for SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) and blood samples were tested for IgG antibodies to the virus. RESULTS: 21 children and adolescents (median age 7.9 (range 3.7-16.6) years) were admitted with features of Kawasaki disease over a 15 day period, with 12 (57%) of African ancestry. 12 (57%) presented with Kawasaki disease shock syndrome and 16 (76%) with myocarditis. 17 (81%) required intensive care support. All 21 patients had noticeable gastrointestinal symptoms during the early stage of illness and high levels of inflammatory markers. 19 (90%) had evidence of recent SARS-CoV-2 infection (positive RT-PCR result in 8/21, positive IgG antibody detection in 19/21). All 21 patients received intravenous immunoglobulin and 10 (48%) also received corticosteroids. The clinical outcome was favourable in all patients. Moderate coronary artery dilations were detected in 5 (24%) of the patients during hospital stay. By 15 May 2020, after 8 (5-17) days of hospital stay, all patients were discharged home. CONCLUSIONS: The ongoing outbreak of Kawasaki-like multisystem inflammatory syndrome among children and adolescents in the Paris area might be related to SARS-CoV-2. In this study an unusually high proportion of the affected children and adolescents had gastrointestinal symptoms, Kawasaki disease shock syndrome, and were of African ancestry.


Asunto(s)
Anticuerpos Antivirales/sangre , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/diagnóstico , Neumonía Viral/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Adolescente , Corticoesteroides/uso terapéutico , Betacoronavirus/genética , Betacoronavirus/inmunología , Niño , Preescolar , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Masculino , Nasofaringe/virología , Pandemias , Paris , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Estudios Prospectivos , ARN Viral/genética , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/etiología
14.
PLoS One ; 15(1): e0227652, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31968009

RESUMEN

BACKGROUND: Early recognition of sepsis is critical for timely initiation of treatment. The first objective of this study was to assess the timeliness of diagnostic procedures for recognizing sepsis in emergency departments. We define diagnostic procedures as tests used to help diagnose the condition of patients. The second objective was to estimate associations between diagnostic procedures and time to antibiotic treatment, and to estimate associations between time to antibiotic treatment and mortality. METHODS: This observational study from 24 emergency departments in Norway included 1559 patients with infection and at least two systemic inflammatory response syndrome criteria. We estimated associations using linear and logistic regression analyses. RESULTS: Of the study patients, 72.9% (CI 70.7-75.1) had documented triage within 15 minutes of presentation to the emergency departments, 44.9% (42.4-47.4) were examined by a physician in accordance with the triage priority, 44.4% (41.4-46.9) were adequately observed through continual monitoring of signs while in the emergency department, and 25.4% (23.2-27.7) received antibiotics within 1 hour. Delay or non-completion of these key diagnostic procedures predicted a delay of more than 2.5 hours to antibiotic treatment. Patients who received antibiotics within 1 hour had an observed 30-day all-cause mortality of 13.6% (10.1-17.1), in the timespan 2 to 3 hours after admission 5.9% (2.8-9.1), and 4 hours or later after admission 10.5% (5.7-15.3). CONCLUSIONS: Key procedures for recognizing sepsis were delayed or not completed in a substantial proportion of patients admitted to the emergency department with sepsis. Delay or non-completion of key diagnostic procedures was associated with prolonged time to treatment with antibiotics. This suggests a need for systematic improvement in the initial management of patients admitted to emergency departments with sepsis.


Asunto(s)
Servicio de Urgencia en Hospital , Sepsis/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Diagnóstico Precoz , Servicio de Urgencia en Hospital/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/mortalidad , Tiempo de Tratamiento , Triaje , Adulto Joven
15.
Gastroenterology ; 158(1): 253-269.e14, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31593700

RESUMEN

BACKGROUND & AIMS: Pancreatitis starts with primarily sterile local inflammation that induces systemic inflammatory response syndrome, followed by compensatory anti-inflammatory response syndrome (CARS). We investigated the mechanisms of these processes in mice and human serum. METHODS: We induced severe acute pancreatitis by partial duct ligation with caerulein stimulation or intraperitoneal injection of l-arginine in mice with deletion of interleukin (IL)12B, NLRP3, or IL18 and in mice given MCC950, a small molecule inhibitor of the NLRP3-inflammasome. Pancreata were collected from mice and analyzed by histology, and cytokine levels were measured in serum samples. We measured activation of adaptive immune responses in mice with pancreatitis by flow cytometry analysis of T cells (CD25 and CD69) isolated from the spleen. Differentiation of T-helper (Th1) cells, Th2 cells, and T-regulatory cells was determined by nuclear staining for TBET, GATA3, and FOXP3. We performed transcriptome analysis of mouse lymph nodes and bone marrow-derived macrophages after incubation with acini. We measured levels of cytokines in serum samples from patients with mild and severe acute pancreatitis. RESULTS: Activation of the adaptive immune response in mice was initiated by macrophage-derived, caspase 1-processed cytokines and required activation of NLRP3 (confirmed in serum samples from patients with pancreatitis). Spleen cells from mice with pancreatitis had increases in Th2 cells but not in Th1 cells. Bone marrow-derived macrophages secreted IL1B and IL18, but not IL12, after co-incubation with pancreatic acini. T-cell activation and severity of acute pancreatitis did not differ significantly between IL12B-deficient and control mice. In contrast, NLRP3- or IL18-deficient mice had reduced activation of T cells and no increase in Th2 cell-mediated responses compared with control mice. The systemic type 2 immune response was mediated by macrophage-derived cytokines of the IL1 family. Specifically, IL18 induced a Th2 cell-mediated response in the absence of IL12. MCC950 significantly reduced neutrophil infiltration, T-cell activation, and disease severity in mice. CONCLUSIONS: In mice with severe pancreatitis, we found systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome developed in parallel. Infiltrating macrophages promote inflammation and simultaneously induce a Th2 cell-mediated response via IL18. Inhibition of NLRP3 reduces systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome and might be used to treat patients with severe pancreatitis.


Asunto(s)
Furanos/administración & dosificación , Inflamasomas/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Pancreatitis/inmunología , Sulfonamidas/administración & dosificación , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Células Acinares , Inmunidad Adaptativa , Animales , Arginina/toxicidad , Células Cultivadas , Ceruletida/toxicidad , Citocinas/sangre , Citocinas/inmunología , Modelos Animales de Enfermedad , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Inyecciones Intraperitoneales , Interleucina-18/inmunología , Interleucina-18/metabolismo , Macrófagos/inmunología , Ratones , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Páncreas/citología , Páncreas/inmunología , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/tratamiento farmacológico , Cultivo Primario de Células , Sulfonas , Síndrome de Respuesta Inflamatoria Sistémica/sangre , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Células Th2/inmunología , Células Th2/metabolismo
16.
J Pediatric Infect Dis Soc ; 9(1): 36-43, 2020 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-30476186

RESUMEN

BACKGROUND: Biomarkers can facilitate safe antibiotic discontinuation in critically ill patients without bacterial infection. METHODS: We tested the ability of a biomarker-based algorithm to reduce excess antibiotic administration in patients with systemic inflammatory response syndrome (SIRS) without bacterial infections (uninfected) in our pediatric intensive care unit (PICU). The algorithm suggested that PICU clinicians stop antibiotics if (1) C-reactive protein <4 mg/dL and procalcitonin <1 ng/mL at SIRS onset and (2) no evidence of bacterial infection by exam/testing by 48 hours. We evaluated excess broad-spectrum antibiotic use, defined as administration on days 3-9 after SIRS onset in uninfected children. Incidence rate ratios (IRRs) compared unadjusted excess length of therapy (LOT) in the 34 months before (Period 1) and 12 months after (Period 2) implementation of this algorithm, stratified by biomarker values. Segmented linear regression evaluated excess LOT among all uninfected episodes over time and between the periods. RESULTS: We identified 457 eligible SIRS episodes without bacterial infection, 333 in Period 1 and 124 in Period 2. When both biomarkers were below the algorithm's cut-points (n = 48 Period 1, n = 31 Period 2), unadjusted excess LOT was lower in Period 2 (IRR, 0.53; 95% confidence interval, 0.30-0.93). Among all 457 uninfected episodes, there were no significant differences in LOT (coefficient 0.9, P = .99) between the periods on segmented regression. CONCLUSIONS: Implementation of a biomarker-based algorithm did not decrease overall antibiotic exposure among all uninfected patients in our PICU, although exposures were reduced in the subset of SIRS episodes where biomarkers were low.


Asunto(s)
Algoritmos , Antibacterianos/uso terapéutico , Programas de Optimización del Uso de los Antimicrobianos , Proteína C-Reactiva/análisis , Polipéptido alfa Relacionado con Calcitonina/sangre , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Adolescente , Infecciones Bacterianas/diagnóstico , Biomarcadores/sangre , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Unidades de Cuidado Intensivo Pediátrico , Modelos Lineales , Masculino , Sepsis/diagnóstico , Factores de Tiempo
18.
Ann Surg Oncol ; 27(3): 898-906, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31792715

RESUMEN

BACKGROUND: The systemic immune-inflammation index (SII), calculated using absolute platelet, neutrophil, and lymphocyte counts, has recently emerged as a predictor of survival for patients with pancreatic ductal adenocarcinoma (PDAC) when assessed at diagnosis. Neoadjuvant therapy (NAT) is increasingly used in the treatment of PDAC. However, biomarkers of response are lacking. This study aimed to determine the prognostic significance of SII before and after NAT and its association with the pancreatic tumor biomarker carbohydrate-antigen 19-9 (CA 19-9). METHODS: This study retrospectively analyzed all PDAC patients treated with NAT before pancreatic resection at a single institution between 2007 and 2017. Pre- and post-NAT lab values were collected to calculate SII. Absolute pre-NAT, post-NAT, and change in SII after NAT were evaluated for their association with clinical outcomes. RESULTS: The study analyzed 419 patients and found no significant correlation between pre-NAT SII and clinical outcomes. Elevated post-NAT SII was an independent, negative predictor of overall survival (OS) when assessed as a continuous variable (hazard ratio [HR], 1.0001; 95% confidence interval [CI] 1.00003-1.00014; p = 0.006). Patients with a post-NAT SII greater than 900 had a shorter median OS (31.9 vs 26.1 months; p = 0.050), and a post-NAT SII greater than 900 also was an independent negative predictor of OS (HR, 1.369; 95% CI 1.019-1.838; p = 0.037). An 80% reduction in SII independently predicted a CA 19-9 response after NAT (HR, 4.22; 95% CI 1.209-14.750; p = 0.024). CONCLUSION: Post-treatment SII may be a useful prognostic marker in PDAC patients receiving NAT.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/patología , Terapia Neoadyuvante/mortalidad , Neoplasias Pancreáticas/patología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Anciano , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pancreatectomía/métodos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/inmunología
19.
Cell Death Dis ; 10(7): 493, 2019 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-31235688

RESUMEN

Necroptosis is a form of regulated necrosis controlled by receptor-interacting kinase 1 (RIPK1 or RIP1), RIPK3 (RIP3), and pseudokinase mixed lineage kinase domain-like protein (MLKL). Increasing evidence suggests that necroptosis is closely associated with pathologies including inflammatory diseases, neurodegenerative diseases, and cancer metastasis. Herein, we discovered the small-molecule PK6 and its derivatives as a novel class of necroptosis inhibitors that directly block the kinase activity of RIPK1. Optimization of PK6 led to PK68, which has improved efficacy for the inhibition of RIPK1-dependent necroptosis, with an EC50 of around 14-22 nM in human and mouse cells. PK68 efficiently blocks cellular activation of RIPK1, RIPK3, and MLKL upon necroptosis stimuli. PK68 displays reasonable selectivity for inhibition of RIPK1 kinase activity and favorable pharmacokinetic properties. Importantly, PK68 provides strong protection against TNF-α-induced systemic inflammatory response syndrome in vivo. Moreover, pre-treatment of PK68 significantly represses metastasis of both melanoma cells and lung carcinoma cells in mice. Together, our study demonstrates that PK68 is a potent and selective inhibitor of RIPK1 and also highlights its great potential for use in the treatment of inflammatory disorders and cancer metastasis.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Necroptosis/efectos de los fármacos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Factor de Necrosis Tumoral alfa/toxicidad , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células HT29 , Humanos , Masculino , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Necrosis/metabolismo , Proteínas Quinasas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Células U937
20.
BJU Int ; 124(3): 496-503, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31136070

RESUMEN

OBJECTIVE: To study the incidence of postoperative systemic inflammatory response syndrome (SIRS) following different antibiotic prophylaxis (ABP) regimens in retrograde intrarenal surgery (RIRS). PATIENTS AND METHODS: Single-centre, randomised, controlled trial (August 2014-September 2017) including 426 patients with renal stones with preoperative sterile urine managed by RIRS (ClinicalTrials.gov NCT02304822). Different ciprofloxacin-based ABP regimens were used and included a zero dose, single dose (30 min before surgery) or two doses (first dose at 30 min before RIRS and additional dose within 6 h after RIRS). The incidence of SIRS was compared using intention-to-treat (ITT) and per-protocol (PP) analyses. RESULTS: Each group enrolled 142 patients. In the ITT analysis, a zero dose of ABP was statistically similar to the two ABP regimes for the incidence of SIRS (9.9% vs single dose 4.9%, P = 0.112; vs two doses 4.2%, P = 0.062). There were also no relevant differences across groups in the PP analysis; no urosepsis was recorded. In subgroup analysis with stratification by stone area, the three regimens all had a low and similar incidence of SIRS for stones of ≤200 mm2 in the ITT analysis with a sufficient power value (5.4% vs 6.2% vs 3.6%, P = 0.945 vs single dose and P = 0.553 vs two doses). However, there was a greater chance of SIRS in patients who received no ABP with stones of >200 mm2 (18% vs single dose 4.3%, P = 0.036; vs two doses 5.5%, P = 0.044). Similar trends were seen in the PP analysis. CONCLUSIONS: For patients with preoperative sterile urine, ABP is not strongly recommended in patients with stones of ≤200 mm2 , but for stones >200 mm2 single-dose ABP is still required.


Asunto(s)
Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Cálculos Renales/cirugía , Complicaciones Posoperatorias/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Adulto , Antibacterianos/administración & dosificación , Femenino , Humanos , Incidencia , Riñón/cirugía , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/prevención & control
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