RESUMEN
Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently, neutralising autoantibodies against inflammatory receptor antagonists progranulin and interleukin-1 receptor antagonist (IL-1Ra) were found in adult patients with critical COVID-19. The aim of this study was to investigate the role of such autoantibodies in MIS-C. Methods: In this multicentre, retrospective, cohort study, plasma and serum samples were collected from patients (0-18 years) with MIS-C (as per WHO criteria) treated at five clinical centres in Germany and Spain. As controls, we included plasma or serum samples from children with Kawasaki disease, children with inactive systemic juvenile idiopathic arthritis, and children with suspected growth retardation (non-inflammatory control) across four clinical centres in Germany and Spain (all aged ≤18 years). Serum samples from the CoKiBa trial were used as two further control groups, from healthy children (negative for SARS-CoV-2 antibodies) and children with previous mild or asymptomatic COVID-19 (aged ≤17 years). MIS-C and control samples were analysed for autoantibodies against IL-1Ra and progranulin, and for IL-1Ra concentrations, by ELISA. Biochemical analysis of plasma IL-1Ra was performed with native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signalling reporter assay. Findings: Serum and plasma samples were collected between March 6, 2011, and June 2, 2021. Autoantibodies against IL-1Ra could be detected in 13 (62%) of 21 patients with MIS-C (11 girls and ten boys), but not in children with Kawasaki disease (n=24; nine girls and 15 boys), asymptomatic or mild COVID-19 (n=146; 72 girls and 74 boys), inactive systemic juvenile idiopathic arthritis (n=10; five girls and five boys), suspected growth retardation (n=33; 13 girls and 20 boys), or in healthy controls (n=462; 230 girls and 232 boys). Anti-IL-1Ra antibodies in patients with MIS-C belonged exclusively to the IgG1 subclass, except in one patient who had additional IL-1Ra-specific IgM antibodies. Autoantibodies against progranulin were only detected in one (5%) patient with MIS-C. In patients with MIS-C who were positive for anti-IL-1Ra antibodies, free plasma IL-1Ra concentrations were reduced, and immune-complexes of IL-1Ra were detected. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1Ra was observed in all patients with MIS-C who were positive for anti-IL-1Ra antibodies. Anti-IL-1Ra antibodies impaired IL-1Ra function in reporter cell assays, resulting in amplified IL-1ß signalling. Interpretation: Anti-IL-1Ra autoantibodies were observed in a high proportion of patients with MIS-C and were specific to these patients. Generation of these autoantibodies might be triggered by an atypical, hyperphosphorylated isoform of IL-1Ra. These autoantibodies impair IL-1Ra bioactivity and might thus contribute to increased IL-1ß-signalling in MIS-C. Funding: NanoBioMed fund of the University of Saarland, José Carreras Center for Immuno and Gene Therapy, Dr Rolf M Schwiete Stiftung, Staatskanzlei Saarland, German Heart Foundation, Charity of the Blue Sisters, Bavarian Ministry of Health, the Center for Interdisciplinary Clinical Research at University Hospital Münster, EU Horizon 2020.
RESUMEN
Multisystem inflammatory syndrome associated with the SARS-CoV-2 pandemic has recently been described in children (MIS-C), partially overlapping with Kawasaki disease (KD). We hypothesized that (a) MIS-C and prepandemic KD cytokine profiles may be unique and justify the clinical differences observed, and (b) SARS-CoV-2-specific immune complexes (ICs) may explain the immunopathology of MIS-C. Seventy-four children were included: 14 with MIS-C, 9 patients positive for SARS-CoV-2 by PCR without MIS-C (COVID), 14 with prepandemic KD, and 37 healthy controls (HCs). Thirty-four circulating cytokines were quantified in pretreatment serum or plasma samples and the presence of circulating SARS-CoV-2 ICs was evaluated in MIS-C patients. Compared with HCs, the MIS-C and KD groups showed most cytokines to be significantly elevated, with IFN-γ-induced response markers (including IFN-γ, IL-18, and IP-10) and inflammatory monocyte activation markers (including MCP-1, IL-1α, and IL-1RA) being the main triggers of inflammation. In linear discriminant analysis, MIS-C and KD profiles overlapped; however, a subgroup of MIS-C patients (MIS-Cplus) differentiated from the remaining MIS-C patients in IFN-γ, IL-18, GM-CSF, RANTES, IP-10, IL-1α, and SDF-1 and incipient signs of macrophage activation syndrome. Circulating SARS-CoV-2 ICs were not detected in MIS-C patients. Our findings suggest a major role for IFN-γ in the pathogenesis of MIS-C, which may be relevant for therapeutic management.
Asunto(s)
COVID-19/etiología , Citocinas/sangre , Síndrome Mucocutáneo Linfonodular/etiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Adolescente , Anticuerpos Antivirales/sangre , Complejo Antígeno-Anticuerpo/sangre , Antígenos Virales/sangre , COVID-19/inmunología , COVID-19/virología , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Lactante , Interferón gamma/sangre , Masculino , Modelos Inmunológicos , Síndrome Mucocutáneo Linfonodular/inmunología , Pandemias , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/virologíaRESUMEN
INTRODUCCIÓ: El loxoscelisme és un conjunt de manifestacions causades per la picada d'una aranya del gènere Loxosceles, que comprèn més de setanta espècies al món. Es pot presentar de dues formes clíniques: cutània o cutaneovisceral; la segona és més greu I potencialment mortal. L'espècie de Loxosceles que habita a la península Ibèrica és l'aranya bruna mediterrània o Loxosceles rufescens, a la qual s'han atribuït alguns casos de loxoscelisme cutani en població adulta; tanmateix, no s'havien reportat fins ara casos pediàtrics. CAS CLÍNIC: Presentem un cas de cel·lulitis cutània d'aspecte hemorràgic secundari a picada d'aràcnid en una adolescent de 16 anys. La identificació de l'insecte (Loxosceles rufescens) en una fotografia aportada per la pacient va facilitar el diagnòstic de loxoscelisme cutani. COMENTARIS: L'aparició brusca d'una lesió necròtica dèrmica després d'una picada, associada a dolor intens I edema, ens ha de fer sospitar la participació d'aràcnids. El reconeixement d'entitats clíniques com el loxoscelisme pot ajudar a instaurar un tractament precoç que estalviï les possibles complicacions associades, tant locals (necrosis dèrmica) com sistèmiques (anèmia hemolítica, insuficiència renal, coagulació intravascular disseminada, alteracions neurològiques, o fins I tot la mort)
INTRODUCCIÓN: El loxoscelismo es un conjunto de manifestaciones causadas por la picadura de una araña del género Loxosceles, que incluye más de setenta especies en el mundo. Se puede presentar de dos formas clínicas: cutánea o cutánea-visceral, la segunda más grave y potencialmente mortal. La especie de Loxosceles que habita en la Península Ibérica es la araña parda mediterránea o Loxosceles rufescens, a la que se han atribuido algunos casos de loxoscelismo cutáneo en población adulta; sin embargo, no se habían reportado hasta la fecha casos pediátricos. CASO CLÍNICO: Presentamos un caso de celulitis cutánea de aspecto hemorrágico secundario a picadura de arácnido en una adolescente de 16 años. La identificación del insecto (Loxosceles rufescens) en una fotografía aportada por la paciente facilitó el diagnóstico de loxoscelismo cutáneo. COMENTARIOS: La aparición brusca de una lesión necrótica dérmica después de una picadura, asociada a intenso dolor y edema, nos debe hacer sospechar la participación de arácnidos. El reconocimiento de entidades clínicas como el loxoscelismo puede ayudar a instaurar un tratamiento precoz que ahorre las posibles complicaciones asociadas, tanto locales (necrosis dérmica) como sistémicas (anemia hemolítica, insuficiencia renal, coagulación intravascular diseminada, alteraciones neurológicas, o incluso la muerte)
INTRODUCTION: Loxoscelism is a set of manifestations caused by the bite of a spider of the genus Loxosceles, which includes more than 70 species in the world. It can present in two clinical forms: cutaneous or cutaneous-visceral, which is more serious and potentially fatal. The species of Loxosceles that inhabits the Iberian Peninsula is the Mediterranean brown spider or Loxosceles rufescens, to which some cases of cutaneous loxoscelism in the adult population have been attributed; however, pediatric cases have not been reported to date. CASE REPORT: We present a case of cutaneous cellulitis with hemorrha gic appearance secondary to arachnid bite in a 16-year-old adolescent. The identification of the insect (Loxosceles rufescens) in a photograph provided by the patient facilitated the diagnosis of cutaneous loxoscelism. COMMENTS: The sudden appearance of a dermal necrotic lesion after a bite, associated with intense pain and edema, should make us suspect a spider bite. The recognition of clinical entities such as loxoscelism can help to establish an early treatment that avoids the possible associated complications, both local (dermal necrosis) and systemic (hemolytic anemia, renal insufficiency, disseminated intravascular coagulation, neurological alterations, or death