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

ABSTRACT

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.


Subject(s)
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
3.
Blood ; 136(Supplement 1):28-29, 2020.
Article in English | PMC | ID: covidwho-1338970

ABSTRACT

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

4.
J Pediatric Infect Dis Soc ; 10(5): 669-673, 2021 May 28.
Article in English | MEDLINE | ID: covidwho-1262143

ABSTRACT

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike immunoglobulin G (IgG) titers compared with those with severe coronavirus disease 2019, likely reflecting a longer time since the onset of infection in MIS-C patients.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation , COVID-19/immunology , Spike Glycoprotein, Coronavirus/immunology , Systemic Inflammatory Response Syndrome/immunology , COVID-19 Serological Testing , Child , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Male , SARS-CoV-2 , Severity of Illness Index
5.
Sci Immunol ; 6(57)2021 03 02.
Article in English | MEDLINE | ID: covidwho-1115087

ABSTRACT

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.


Subject(s)
COVID-19/immunology , Lymphocyte Activation , Systemic Inflammatory Response Syndrome/immunology , T-Lymphocytes/immunology , Adolescent , Adult , Aging/immunology , Child , Child, Preschool , Female , Flow Cytometry , Humans , Leukopenia/immunology , Male , Young Adult
7.
Blood Adv ; 4(23): 6051-6063, 2020 12 08.
Article in English | MEDLINE | ID: covidwho-962802

ABSTRACT

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.


Subject(s)
COVID-19/diagnosis , Thrombotic Microangiopathies/diagnosis , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Adolescent , Antibodies, Viral/blood , Biomarkers/metabolism , COVID-19/pathology , COVID-19/virology , Child , Child, Preschool , Cluster Analysis , Complement Membrane Attack Complex/metabolism , Creatinine/blood , Female , Humans , Male , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Severity of Illness Index , Thrombotic Microangiopathies/complications
8.
medRxiv ; 2020 Aug 18.
Article in English | MEDLINE | ID: covidwho-900749

ABSTRACT

SARS-CoV-2 antibody responses in children remain poorly characterized. Here, we show that pediatric patients with multisystem inflammatory syndrome in children (MIS-C) possess higher SARS-CoV-2 spike IgG titers compared to those with severe coronavirus disease 2019 (COVID-19), likely reflecting a longer time since onset of infection in MIS-C patients.

9.
medRxiv ; 2020 Oct 06.
Article in English | MEDLINE | ID: covidwho-807631

ABSTRACT

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8 T cells that correlated with use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct and implicate CD8 T cells in clinical presentation and trajectory of MIS-C.

10.
J Clin Invest ; 130(11): 5967-5975, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-690425

ABSTRACT

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.


Subject(s)
Betacoronavirus/metabolism , Complement Membrane Attack Complex/metabolism , Coronavirus Infections , Cytokines/blood , Pandemics , Pneumonia, Viral , Systemic Inflammatory Response Syndrome , Adolescent , COVID-19 , Child , Child, Preschool , Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Female , Humans , Male , Pneumonia, Viral/blood , Pneumonia, Viral/epidemiology , Prospective Studies , SARS-CoV-2 , Severity of Illness Index , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/epidemiology
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