Autoantibodies against interleukin-1 receptor antagonist in multisystem inflammatory syndrome in children: a multicentre, retrospective, cohort study.

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.

Documento español de consenso sobre diagnóstico, estabilización y tratamiento del síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2 (SIM-PedS) / Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS)

Se ha descrito un nuevo síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2. Este cuadro presenta una expresividad clínica variable y se asocia a infección activa o reciente por SARS-CoV-2. En este documento se revisa la literatura existente por parte de un grupo multidisciplinar de especialistas pediátricos. Posteriormente, se realizan recomendaciones sobre estabilización, diagnóstico y tratamiento de este síndrome

A new paediatric multisystem inflammatory syndrome, linked to SARS-CoV-2, has been described. The clinical picture is variable and is associated with an active or recent infection due to SARS-CoV-2. A review of the existing literature by a multidisciplinary group of paediatric specialists is presented in this document. Later, they make recommendations on the stabilisation, diagnosis, and treatment of this síndrome

Similarities and differences between the immunopathogenesis of COVID-19-related pediatric multisystem inflammatory syndrome and Kawasaki disease.

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.

[Spanish consensus document on diagnosis, stabilisation and treatment of pediatric multisystem inflammatory syndrome related to SARS-CoV-2 (SIM-PedS)]. / Documento español de consenso sobre diagnóstico, estabilización y tratamiento del síndrome inflamatorio multisistémico pediátrico vinculado a SARS-CoV-2 (SIM-PedS).

A new paediatric multisystem inflammatory syndrome, linked to SARS-CoV-2, has been described. The clinical picture is variable and is associated with an active or recent infection due to SARS-CoV-2. A review of the existing literature by a multidisciplinary group of paediatric specialists is presented in this document. Later, they make recommendations on the stabilisation, diagnosis, and treatment of this syndrome.

Cel·lulitis cutània d'evolució tòrpida: loxoscelisme cutani / Celulitis cutánea de evolución tórpida: loxoscelismo cutáneo / Cutaneous cellulitis of torpid evolution: cutaneous loxocelism

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

Hyaline fibromatosis syndrome: Clinical update and phenotype-genotype correlations.

Hyaline fibromatosis syndrome (HFS) is the unifying term for infantile systemic hyalinosis and juvenile hyaline fibromatosis. HFS is a rare autosomal recessive disorder of the connective tissue caused by mutations in the gene for anthrax toxin receptor-2 (ANTXR2). It is characterized by abnormal growth of hyalinized fibrous tissue with cutaneous, mucosal, osteoarticular, and systemic involvement. We reviewed the 84 published cases and their molecular findings, aiming to gain insight into the clinical features, prognostic factors, and phenotype-genotype correlations. Extreme pain at minimal handling in a newborn is the presentation pattern most frequently seen in grade 4 patients (life-limiting disease). Gingival hypertrophy and subcutaneous nodules are some of the disease hallmarks. Though painful joint stiffness and contractures are almost universal, weakness and hypotonia may also be present. Causes of death are intractable diarrhea, recurrent infections, and organ failure. Median age of death of grade 4 cases is 15.0 months (p25-p75: 9.5-24.0). This review provides evidence to reinforce the previous hypothesis that missense mutations in exons 1-12 and mutations leading to a premature stop codon lead to the severe form of the disease, while missense pathogenic variants in exons 13-17 lead to the mild form of the disease. Multidisciplinary team approach is recommended.

Benign afebrile convulsions in the course of mild acute gastroenteritis: a study of 28 patients and a literature review.

OBJECTIVES: Since the description of afebrile convulsions in the course of mild acute gastroenteritis (AGE) in 1982 by Morooka in Japan, there have been few reports of further cases outside Asia. The aim of this study was to share our casuistry--from a non-Asian country. METHODS: This is a retrospective study of identified cases in our center from January 2002 to December 2007. RESULTS: A total of 28 patients were studied. All were previously healthy patients who experienced convulsions with mild AGE without dehydration and with normal blood analysis. The mean age was 17.25 months (range, 6-48 months), with 93% younger than 24 months. Seizures were generalized tonic-clonic (61%), followed by generalized tonic (31%), and hypotonic (5.2%), with 2 (2.6%) partial. Only 8 patients (28.6%) presented one convulsion, and in 13 patients (46%), the seizures were in clusters from 3 to 6. Eleven patients (39%) presented 2 different types of convulsion. The duration of the crises ranged from 30 seconds to 10 minutes, and all of them occurred within 24 hours of the first. Electroencephalograms, obtained for all patients, were normal. Rotavirus was the main infectious agent in the AGEs, found in 11 patients with 22 determinations. In one patient, Salmonella serotype Enteritidis was isolated. All of the patients developed favorably, with no sequelae or epilepsy during the follow-up period. CONCLUSIONS: Afebrile convulsion in the course of mild gastroenteritis exists in our environment. It is a banal symptom in the course of the disease with good prognosis. Recognition of this fact may help avoid needless explorations and treatment in patients of this kind.