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1.
Cell ; 183(4): 982-995.e14, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-32991843

RESUMEN

Initially, children were thought to be spared from disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a month into the epidemic, a novel multisystem inflammatory syndrome in children (MIS-C) emerged. Herein, we report on the immune profiles of nine MIS-C cases. All MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with intact neutralization capability. Cytokine profiling identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1), and mucosal immune dysregulation (IL-17A, CCL20, and CCL28). Immunophenotyping of peripheral blood revealed reductions of non-classical monocytes, and subsets of NK and T lymphocytes, suggesting extravasation to affected tissues. Finally, profiling the autoantigen reactivity of MIS-C plasma revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal, and immune-cell antigens. All patients were treated with anti-IL-6R antibody and/or IVIG, which led to rapid disease resolution.


Asunto(s)
Inflamación/patología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Adolescente , Anticuerpos Antivirales/sangre , Autoanticuerpos/sangre , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , COVID-19 , Quimiocina CCL3/metabolismo , Niño , Preescolar , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Femenino , Humanos , Inmunidad Humoral , Lactante , Recién Nacido , Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucina-18/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Masculino , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/patología , Neumonía Viral/virología , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Linfocitos T/citología , Linfocitos T/metabolismo , Adulto Joven
3.
Surg Endosc ; 36(6): 4290-4298, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-34988744

RESUMEN

BACKGROUND: Ileal Crohn's disease (CD) complicated by intraabdominal abscess, phlegmon, fistula, and/or microperforation is commonly treated with antibiotics, bowel rest, and percutaneous drainage followed by interval ileocolic resection (ICR). This "cool off" strategy is intended to facilitate the safe completion of a one-stage resection using a minimally invasive approach and minimize perioperative complications. There is limited data evaluating the benefits of delayed versus early resection. METHODS: A retrospective review of a prospectively maintained inflammatory bowel disease (IBD) database at a tertiary center was queried from 2013-2020 to identify patients who underwent ICR for complicated ileal CD confirmed on preoperative imaging. ICR cohorts were classified as early (≤ 7 days) vs delayed (> 7 days) based on the interval from diagnostic imaging to surgery. Operative approach and 30-day postoperative morbidity were analyzed. RESULTS: Out of 474 patients who underwent ICR over the 7-year period, 112 patients had complicated ileal CD including 99 patients (88%) with intraabdominal abscess. Early ICR was performed in 52 patients (46%) at a median of 3 days (IQR 2, 5) from diagnostic imaging. Delayed ICR was performed in 60 patients (54%) following a median "cool off" period of 23 days of non-operative treatment (IQR 14, 44), including preoperative percutaneous abscess drainage in 17 patients (28%). A higher proportion of patients with intraabdominal abscess underwent delayed vs early ICR (57% vs 43%, p = 0.19). Overall, there were no significant differences in the rate of laparoscopy (96% vs 90%), conversion to open surgery (12% vs 17%), rates of extended bowel resection (8% vs 13%), additional concurrent procedures (44% vs 52%), or fecal diversion (10% vs 2%) in the early vs delayed ICR groups. The median postoperative length of stay was 5 days in both groups with an overall 25% vs 17% (p = 0.39) 30-day postoperative complication rate and a 6% vs 5% 30-day readmission rate in early vs delayed ICR groups, respectively. Overall median follow-up time was 14.3 months (IQR 1.2, 24.1) with no difference in the rate of subsequent CD-related intestinal resection (4% vs 5%) between the two groups. CONCLUSIONS: In this contemporary series, at a high-volume tertiary referral center, a "cool off" delayed resectional approach was not found to reduce perioperative complications in patients undergoing ICR for complicated ileal Crohn's disease. Laparoscopic ICR can be performed within one week of diagnosis with low rates of conversion and postoperative complications.


Asunto(s)
Absceso Abdominal , Enfermedad de Crohn , Laparoscopía , Absceso Abdominal/etiología , Absceso Abdominal/cirugía , Absceso/etiología , Absceso/cirugía , Anastomosis Quirúrgica/efectos adversos , Colectomía/efectos adversos , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/cirugía , Humanos , Laparoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Resultado del Tratamiento
4.
Nat Commun ; 12(1): 4854, 2021 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-34381049

RESUMEN

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Transcriptoma/inmunología , Adolescente , Antígeno CD56/metabolismo , Antígenos CD57/metabolismo , Linfocitos T CD8-positivos/metabolismo , COVID-19/genética , Niño , Preescolar , Regulación hacia Abajo , Femenino , Humanos , Lactante , Recién Nacido , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Síndrome Mucocutáneo Linfonodular/genética , Síndrome Mucocutáneo Linfonodular/inmunología , SARS-CoV-2/patogenicidad , Síndrome de Respuesta Inflamatoria Sistémica/genética , Adulto Joven
5.
medRxiv ; 2020 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-32676612

RESUMEN

Initially, the global outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spared children from severe disease. However, after the initial wave of infections, clusters of a novel hyperinflammatory disease have been reported in regions with ongoing SARS-CoV-2 epidemics. While the characteristic clinical features are becoming clear, the pathophysiology remains unknown. Herein, we report on the immune profiles of eight Multisystem Inflammatory Syndrome in Children (MIS-C) cases. We document that all MIS-C patients had evidence of prior SARS-CoV-2 exposure, mounting an antibody response with normal isotype-switching and neutralization capability. We further profiled the secreted immune response by high-dimensional cytokine assays, which identified elevated signatures of inflammation (IL-18 and IL-6), lymphocytic and myeloid chemotaxis and activation (CCL3, CCL4, and CDCP1) and mucosal immune dysregulation (IL-17A, CCL20, CCL28). Mass cytometry immunophenotyping of peripheral blood revealed reductions of mDC1 and non-classical monocytes, as well as both NK- and T- lymphocytes, suggesting extravasation to affected tissues. Markers of activated myeloid function were also evident, including upregulation of ICAM1 and FcγR1 in neutrophil and non-classical monocytes, well-documented markers in autoinflammation and autoimmunity that indicate enhanced antigen presentation and Fc-mediated responses. Finally, to assess the role for autoimmunity secondary to infection, we profiled the auto-antigen reactivity of MIS-C plasma, which revealed both known disease-associated autoantibodies (anti-La) and novel candidates that recognize endothelial, gastrointestinal and immune-cell antigens. All patients were treated with anti-IL6R antibody or IVIG, which led to rapid disease resolution tracking with normalization of inflammatory markers.

7.
medRxiv ; 2020 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-32909006

RESUMEN

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8 + T-cells and CD56 dim CD57 + NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21 , a central coordinator of exhausted CD8 + T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.

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