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1.
Nat Commun ; 13(1): 2979, 2022 05 27.
Article in English | MEDLINE | ID: covidwho-1931398

ABSTRACT

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (<5, 5-11, 12-21 years) in 177 pediatric patients hospitalized with severe acute COVID-19, acute MIS-C, and in convalescent samples of outpatients with mild COVID-19 during 2020 and early 2021. Across all patients, less than 10% show neutralizing antibody titers against Omicron. Children <5 years of age hospitalized with severe acute COVID-19 have lower neutralizing antibodies to SARS-CoV-2 variants compared with patients >5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.


Subject(s)
COVID-19 , SARS-CoV-2 , Adolescent , Antibodies, Viral , COVID-19/complications , Child , Child, Preschool , Humans , Membrane Glycoproteins , Neutralization Tests , Spike Glycoprotein, Coronavirus , Systemic Inflammatory Response Syndrome , Viral Envelope Proteins
2.
Int J Mol Sci ; 23(13)2022 Jun 29.
Article in English | MEDLINE | ID: covidwho-1917515

ABSTRACT

We studied SARS-CoV-2-specific T cell responses in 22 subacute MIS-C children enrolled in 2021 and 2022 using peptide pools derived from SARS-CoV-2 spike or nonspike proteins. CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in 5 subjects, CD4+ T helper (Th) responses alone were detected in 12 subjects, and CD8+ cytotoxic T cell (CTL) responses alone were documented in 1 subject. Notably, a sizeable subpopulation of CD4- CD8- double-negative (DN) T cells out of total CD3+ T cells was observed in MIS-C (median: 14.5%; IQR 8.65-25.3) and recognized SARS-CoV-2 peptides. T cells bearing the Vß21.3 T cell receptor (TcRs), previously reported as pathogenic in the context of MIS-C, were detected in high frequencies, namely, in 2.8% and 3.9% of the CD4+ and CD8+ T cells, respectively. However, Vß21.3 CD8+ T cells that responded to SARS-CoV-2 peptides were detected in only a single subject, suggesting recognition of nonviral antigens in the majority of subjects. Subjects studied 6-14 months after MIS-C showed T cell epitope spreading, meaning the activation of T cells that recognize more SARS-CoV-2 peptides following the initial expansion of T cells that see immunodominant epitopes. For example, subjects that did not recognize nonspike proteins in the subacute phase of MIS-C showed good Th response to nonspike peptides, and/or CD8+ T cell responses not appreciable before arose over time and could be detected in the 6-14 months' follow-up. The magnitude of the Th and CTL responses also increased over time. In summary, patients with MIS-C associated with acute lymphopenia, a classical feature of MIS-C, showed a physiological response to the virus with a prominent role for virus-specific DN T cells.


Subject(s)
COVID-19 , SARS-CoV-2 , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , COVID-19/complications , Child , Humans , Peptides/metabolism , Systemic Inflammatory Response Syndrome
3.
Clin Infect Dis ; 2022 Apr 21.
Article in English | MEDLINE | ID: covidwho-1915538

ABSTRACT

Our study demonstrates that children who developed SARS-CoV-2 vaccination-induced myocarditis and may not receive another vaccination, could be susceptible to infection with Omicron and emerging variants. We observed higher neutralizing antibody titers in myocarditis patients vs. healthy vaccinated children, but significantly lower neutralization titers against Omicron in both groups.

4.
JAMA Netw Open ; 5(6): e2217436, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1898503

ABSTRACT

Importance: Public health measures implemented during the COVID-19 pandemic had widespread effects on population behaviors, transmission of infectious diseases, and exposures to environmental pollutants. This provided an opportunity to study how these factors potentially influenced the incidence of Kawasaki disease (KD), a self-limited pediatric vasculitis of unknown etiology. Objectives: To examine the change in KD incidence across the United States and evaluate whether public health measures affected the prevalence of KD. Design, Setting, and Participants: This multicenter cohort study included consecutive, unselected patients with KD who were diagnosed between January 1, 2018, and December 31, 2020 (multicenter cohort with 28 pediatric centers), and a detailed analysis of patients with KD who were diagnosed between January 1, 2002, and November 15, 2021 (Rady Children's Hospital San Diego [RCHSD]). Main Outcomes and Measures: For the multicenter cohort, the date of fever onset for each patient with KD was collected. For RCHSD, detailed demographic and clinical data as well as publicly available, anonymized mobile phone data and median household income by census block group were collected. The study hypothesis was that public health measures undertaken during the pandemic would reduce exposure to the airborne trigger(s) of KD and that communities with high shelter-in-place compliance would experience the greatest decrease in KD incidence. Results: A total of 2461 KD cases were included in the multicenter study (2018: 894; 2019: 905; 2020: 646), and 1461 cases (median [IQR] age, 2.8 years [1.4-4.9 years]; 900 [61.6%] males; 220 [15.1%] Asian, 512 [35.0%] Hispanic, and 338 [23.1%] White children) from RCHSD between 2002 and 2021 were also included. The 28.2% decline in KD cases nationally during 2020 (646 cases) compared with 2018 (894 cases) and 2019 (905 cases) was uneven across the United States. For RCHSD, there was a disproportionate decline in KD cases in 2020 to 2021 compared with the mean (SD) number of cases in earlier years for children aged 1 to 5 years (22 vs 44.9 [9.9]; P = .02), male children (21 vs 47.6 [10.0]; P = .01), and Asian children (4 vs 11.8 [4.4]; P = .046). Mobility data did not suggest that shelter-in-place measures were associated with the number of KD cases. Clinical features including strawberry tongue, enlarged cervical lymph node, and subacute periungual desquamation were decreased during 2020 compared with the baseline period (strawberry tongue: 39% vs 63%; P = .04; enlarged lymph node: 21% vs 32%; P = .09; periungual desquamation: 47% vs 58%; P = .16). School closures, masking mandates, decreased ambient pollution, and decreased circulation of respiratory viruses all overlapped to different extents with the period of decreased KD cases. KD in San Diego rebounded in the spring of 2021, coincident with lifting of mask mandates. Conclusions and Relevance: In this study of epidemiological and clinical features of KD during the COVID-19 pandemic in the United States, KD cases fell and remained low during the period of masking and school closure. Mobility data indicated that differential intensity of sheltering in place was not associated with KD incidence. These findings suggest that social behavior is associated with exposure to the agent(s) that trigger KD and are consistent with a respiratory portal of entry for the agent(s).


Subject(s)
COVID-19 , Mucocutaneous Lymph Node Syndrome , COVID-19/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Fever/epidemiology , Humans , Male , Mucocutaneous Lymph Node Syndrome/epidemiology , Pandemics , United States/epidemiology
5.
Front Immunol ; 13: 841126, 2022.
Article in English | MEDLINE | ID: covidwho-1775675

ABSTRACT

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.


Subject(s)
Autoimmune Diseases , COVID-19 , Lupus Erythematosus, Systemic , Adaptor Proteins, Signal Transducing , Adenosine Triphosphatases , Adult , Autoantibodies , Autoantigens , Autoimmunity , COVID-19/complications , Child , Humans , Immunoglobulins, Intravenous , Ribonucleoproteins , Systemic Inflammatory Response Syndrome
6.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327497

ABSTRACT

Background Multisystem inflammatory syndrome in children (MIS-C) is a novel disease identified during the COVID-19 pandemic characterized by systemic inflammation following SARS-CoV-2 infection. Delays in diagnosing MIS-C may lead to more severe disease with cardiac dysfunction or death. Most pediatric patients recover fully with anti-inflammatory treatments, but early detection of MIS-C remains a challenge given its clinical similarities to Kawasaki disease (KD) and other acute childhood illnesses. Methods We developed KIDMATCH ( K awasak I D isease vs M ultisystem Infl A mma T ory syndrome in CH ildren), a deep learning algorithm for screening patients for MIS-C, KD, or other febrile illness, using age, the five classical clinical KD signs, and 17 laboratory measurements prospectively collected within 24 hours of admission to the emergency department from 1448 patients diagnosed with KD or other febrile illness between January 1, 2009 and December 31, 2019 at Rady Children’s Hospital. For MIS-C patients, the same data was collected from 131 patients between May 14, 2020 to June 18, 2021 at Rady Children’s Hospital, Connecticut Children’s Hospital, and Children’s Hospital Los Angeles. We trained a two-stage model consisting of feedforward neural networks to distinguish between MIS-C and non MIS-C patients and then KD and other febrile illness. After internally validating the algorithm using 10-fold cross validation, we incorporated a conformal prediction framework to tag patients with erroneous data or distribution shifts, enhancing the model generalizability and confidence by flagging unfamiliar cases as indeterminate instead of making spurious predictions. We externally validated KIDMATCH on 175 MIS-C patients from 16 hospitals across the United States. Findings KIDMATCH achieved a high median area under the curve in the 10-fold cross validation of 0.988 [IQR: 0.98-0.993] in the first stage and 0.96 [IQR: 0.956-0.972] in the second stage using thresholds set at 95% sensitivity to detect positive MIS-C and KD cases respectively during training. External validation of KIDMATCH on MIS-C patients correctly classified 76/83 (2 rejected) patients from the CHARMS consortium, 47/50 (1 rejected) patients from Boston Children’s Hospital, and 36/42 (2 rejected) patients from Children’s National Hospital. Interpretation KIDMATCH has the potential to aid frontline clinicians with distinguishing between MIS-C, KD, and similar febrile illnesses in a timely manner to allow prompt treatment and prevent severe complications. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute, National Library of Medicine

7.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295889

ABSTRACT

A significant surge in cases of multisystem inflammatory syndrome in children (MIS-C, also called Pediatric Inflammatory Multisystem Syndrome - PIMS) has been observed amidst the COVID-19 pandemic. MIS-C shares many clinical features with Kawasaki disease (KD), although clinical course and outcomes are divergent. We analyzed whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues from these patients using a computational toolbox of two gene signatures, i.e., the 166-gene viral pandemic (ViP) signature, and its 20-gene severe (s)ViP subset that were developed in the context of SARS-CoV-2 infection and a 13-transcript signature previously demonstrated to be diagnostic for KD. Our analyses revealed that KD and MIS-C are on the same continuum of the host immune response as COVID-19. While both the pediatric syndromes converge upon an IL15/IL15RA -centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis, they diverge in other laboratory parameters and cardiac phenotypes. The ViP signatures also revealed unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to monitor severity.

8.
J Clin Invest ; 131(20)2021 10 15.
Article in English | MEDLINE | ID: covidwho-1470547

ABSTRACT

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1ß have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1ß. Following IVIG treatment, activated IL-1ß+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1ß can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.


Subject(s)
COVID-19/complications , Immunoglobulins, Intravenous/therapeutic use , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/therapy , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/therapy , COVID-19/blood , COVID-19/immunology , COVID-19/therapy , Case-Control Studies , Cell Death/immunology , Cell Lineage/immunology , Child , Child, Preschool , Fas Ligand Protein/immunology , Female , Humans , Infant , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/blood , Leukocyte Count , Male , Mucocutaneous Lymph Node Syndrome/blood , Neutrophil Activation , Neutrophils/classification , Neutrophils/immunology , Neutrophils/pathology , Systemic Inflammatory Response Syndrome/blood
9.
Eur J Immunol ; 52(1): 123-137, 2022 01.
Article in English | MEDLINE | ID: covidwho-1441963

ABSTRACT

The immunopathogenesis of multisystem inflammatory syndrome (MIS-C) in children that may follow exposure to SARS-CoV-2 is incompletely understood. Here, we studied SARS-CoV-2-specific T cells in MIS-C, Kawasaki disease (KD), and SARS-CoV-2 convalescent controls using peptide pools derived from SARS-CoV-2 spike or nonspike proteins, and common cold coronaviruses (CCC). Coordinated CD4+ and CD8+ SARS-CoV-2-specific T cells were detected in five MIS-C subjects with cross-reactivity to CCC. CD4+ and CD8+ T-cell responses alone were documented in three and one subjects, respectively. T-cell specificities in MIS-C did not correlate with disease severity and were similar to SARS-CoV-2 convalescent controls. T-cell memory and cross-reactivity to CCC in MIS-C and SARS-CoV-2 convalescent controls were also similar. The chemokine receptor CCR6, but not CCR9, was highly expressed on SARS-CoV-2-specific CD4+ but not on CD8+ T cells. Only two of 10 KD subjects showed a T-cell response to CCC. Enumeration of myeloid APCs revealed low cell precursors in MIS-C subjects compared to KD. In summary, children with MIS-C mount a normal T-cell response to SARS-CoV-2 with no apparent relationship to antecedent CCC exposure. Low numbers of tolerogenic myeloid DCs may impair their anti-inflammatory response.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/complications , Immunity, Cellular , Immunologic Memory , Mucocutaneous Lymph Node Syndrome , SARS-CoV-2/immunology , Systemic Inflammatory Response Syndrome/immunology , Adolescent , COVID-19/immunology , Child , Child, Preschool , Female , Humans , Infant , Male , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/immunology
11.
JAMA ; 324(3): 259-269, 2020 07 21.
Article in English | MEDLINE | ID: covidwho-574774

ABSTRACT

Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation. Objectives: To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders. Design, Setting, and Participants: Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019. Exposures: Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization. Main Outcomes and Measures: Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders. Results: Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 µg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively). Conclusions and Relevance: In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.


Subject(s)
Coronavirus Infections/complications , Pneumonia, Viral/complications , Symptom Assessment , Systemic Inflammatory Response Syndrome/diagnosis , Adolescent , Betacoronavirus , COVID-19 , Child , Child, Preschool , England , Female , Humans , Male , Mucocutaneous Lymph Node Syndrome/physiopathology , Pandemics , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/physiopathology
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