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Nat Commun ; 12(1): 7222, 2021 12 10.
Article in English | MEDLINE | ID: covidwho-1565718


Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. Here we perform a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesize that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. We show that protein signatures demonstrate overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is an important marker of MIS-C that associates with TMA. We find that IFNγ responses are dysregulated in MIS-C patients, and that IFNγ levels delineate clinical heterogeneity.

COVID-19/complications , Endothelium, Vascular/physiopathology , Interferon-gamma/immunology , Proteome , Systemic Inflammatory Response Syndrome/pathology , Biomarkers , COVID-19/metabolism , COVID-19/pathology , Case-Control Studies , Chemokine CXCL9 , Child , Group II Phospholipases A2 , Humans , Inflammation , Interleukin-10 , Proteomics , Systemic Inflammatory Response Syndrome/metabolism , Vascular Diseases
Blood ; 136(Supplement 1):28-29, 2020.
Article in English | PMC | ID: covidwho-1338970


Introduction: During the Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), 3 distinct phenotypes have emerged in children. The majority of children have mild or no symptoms. Similar to adults, a minority of children can be severely affected with respiratory distress requiring intensive care. Finally, they may develop a phenomenon presumed unique to children termed Multisystem Inflammatory Syndrome in Children (MIS-C). MIS-C is a hyperinflammatory syndrome characterized by fever and organ dysfunction (particularly cardiac) in the setting of recent COVID-19 infection. Reports from the adult literature have invoked thrombotic microangiopathy (TMA) and complement activation as a potential cause for severe manifestations of COVID-19 (Zhang et al. NEJM. 2020;Campbell et al. Circulation 2020). Soluble C5b9 (sC5b-9), the terminal complement complex, has been implicated as a marker of hematopoietic stem cell transplant associated TMA (HSCT-TMA;Jodele et al. Blood 2014). We sought to elucidate the role of terminal complement activation and TMA in the different pediatric disease phenotypes.Methods: We enrolled children admitted to the Children's Hospital of Philadelphia during the COVID-19 pandemic who had evidence of SARS-CoV-2 infection on reverse transcriptase polymerase chain reaction (RT-PCR) from mucosa, or met clinical criteria for MIS-C. Patients (pts) were classified in to 3 categories: minimal COVID-19 symptoms or incidental finding of SARS-CoV-2 infection, severe COVID-19 requiring ventilatory support, or MIS-C. To investigate the role of TMA in children with COVID-19 we measured sC5b-9 in plasma of pts with the 3 manifestations of SARS-CoV-2, and in healthy controls. sC5b9 was measured in triplicate at two dilutions by ELISA. Proinflammatory cytokines were measured using V-Plex Pro-inflammatory Panel 1 Human Kits and analyzed on a QuickPlex SQ120. P-values were computed using Dunn's multiple comparisons test after Kruskal-Wallis testing. Blood smears were examined by a hematologist and hematopathologist for schistocytes.Results: 50 pts were enrolled on whom complete sC5b9 data were available: minimal COVID-19 (N=18), severe COVID-19 (N=11), and MIS-C (N=21). Plasma was obtained on healthy controls (N=26). The median sC5b9 level in healthy controls (57 ng/mL) differed significantly (p<0.001 in each case;Figure 1A) from that in pts with minimal disease (392 ng/mL), severe disease (646 ng/mL), and MIS-C (630 ng/mL);differences between MIS-C, minimal, and severe were not statistically significant. Elevations in sC5b9 correlated in a statistically significant manner with the maximum creatinine and blood urea nitrogen (BUN) measured during hospitalization (Figure 1B&C), but not age (p=0.512). sC5b9 did not correlate with lactate dehydrogenase (LDH), nor with the lowest levels of fibrinogen, hemoglobin or platelet counts. Of pts with available data, 19/26 (73.1%) had elevated LDH, 2/31 (6.4%) had hypofibrinogenemia, 35/47 (74.5%) were anemic, and 28/47 (59.6%) were thrombocytopenic.Pro-inflammatory cytokines were measured. Of particular interest to TMA is the neutrophil chemotactic factor IL-8, because of its role as a marker of endothelial damage (Dvorak et al. Front Pediatr 2019). Levels of IL-8 differed significantly between pts with MIS-C (p=0.0166) or pts with severe COVID-19 (p=0.0079), when compared to minimal COVID-19 pts;but not between pts with MIS-C and severe disease (p = 0.99).Blood smears were available on 34 patients. Schistocytes were present in 13/15 (87%) patients with MIS-C, 7/8 (87%) patients with severe COVID-19 and 5/11 (45%) patients with minimal COVID-19 (χ2=6.59, p=0.037).Conclusions: We demonstrate derangements of the final common pathway of complement activation in children with the 3 presentations of SARS-CoV-2. Strikingly, sC5b9s were abnormal even in children with minimal disease or incidental infection. Renal dysfunction correlated with elevations in sC5b9, strengthening the evidence that TMA plays a role in the pa hophysiology of SARS-CoV-2 infection. Future work is aimed at further characterizing the role of the complement cascade in the pathogenesis of MIS-C and COVID-19 in children. The long-term complications of endothelial damage and complement activation are unknown and extended follow-up is warranted.Figure 1

Pediatr Blood Cancer ; 67(11): e28693, 2020 11.
Article in English | MEDLINE | ID: covidwho-743696


There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.

COVID-19/therapy , Respiratory Distress Syndrome/therapy , Adolescent , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/blood , Antibodies, Viral/therapeutic use , COVID-19/complications , Humans , Immunization, Passive/methods , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Respiratory Distress Syndrome/etiology , SARS-CoV-2/immunology , Severity of Illness Index