Browsing by Author "Chou, Janet"

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    237. A Case-Control Study Investigating Household, Community, and Clinical Risk Factors Associated with Multisystem Inflammatory Syndrome in Children (MIS-C) after SARS-CoV-2 Infection
    (Oxford University Press, 2022) Zambrano, Laura D.; Wu, Michael J.; Martin, Lora M.; Malloch, Lacy; Newhams, Margaret M.; Son, Mary Beth; Sanders, Cameron; Patterson, Kayla; Halasa, Natasha B.; Fitzgerald, Julie C.; Leroue, Matthew; Hall, Mark; Irby, Katherine; Rowan, Courtney M.; Wellnitz, Kari; Loftis, Laura L.; Bradford, Tamara T.; Staat, Mary A.; Babbit, Christopher; Carroll, Christopher L.; Pannaraj, Pia S.; Kong, Michele; Chou, Janet; Patel, Manish M.; Randolph, Adrienne G.; Campbell, Angela P.; Hobbs, Charlotte V.; Medicine, School of Medicine
    Background: Risk factors for MIS-C, a rare but serious hyperinflammatory syndrome associated with SARS-CoV-2 infection, remain unclear. We evaluated household, clinical, and environmental risk factors potentially associated with MIS-C. Methods: This investigation included MIS-C cases hospitalized in 14 US pediatric hospitals in 2021. Outpatient controls were frequency-matched to case-patients by age group and site and had a positive SARS-CoV-2 viral test within 3 months of the admission of their matched MIS-C case (Figure 1). We conducted telephone surveys with caregivers and evaluated potential risk factors using mixed effects multivariable logistic regression, including site as a random effect. We queried regarding exposures within the month before hospitalization for MIS-C cases or the month after a positive COVID-19 test for controls. Enrollment scheme for MIS-C case-patients and SARS-CoV-2-positive outpatient controls. MIS-C case-patients were identified through hospital electronic medical records, while two outpatient controls per case were identified through registries of outpatient SARS-CoV-2 testing logs at facilities affiliated with that medical center. Caregivers of outpatient controls were interviewed at least four weeks after their positive test to ensure they did not develop MIS-C after their infection. Results: We compared 275 MIS-C case-patients with 494 outpatient SARS-CoV-2-positive controls. Race, ethnicity and social vulnerability indices were similar. MIS-C was more likely among persons who resided in households with >1 resident per room (aOR=1.6, 95% CI: 1.1–2.2), attended a large (≥10 people) event with little to no mask-wearing (aOR=2.2, 95% CI: 1.4–3.5), used public transportation (aOR=1.6, 95% CI: 1.2–2.1), attended school >2 days per week with little to no mask wearing (aOR=2.1, 95% CI: 1.0–4.4), or had a household member test positive for COVID-19 (aOR=2.1, 95% CI: 1.3–3.3). MIS-C was less likely among children with comorbidities (aOR=0.5, 95% CI: 0.3–0.9) and in those who had >1 positive SARS-CoV-2 test at least 1 month apart (aOR=0.4, 95% CI: 0.2–0.6). MIS-C was not associated with a medical history of recurrent infections or family history of underlying rheumatologic disease. Conclusion: Household crowding, limited masking at large indoor events or schools and use of public transportation were associated with increased likelihood of developing MIS-C after SARS-CoV-2 infection. In contrast, decreased likelihood of MIS-C was associated with having >1 SARS-CoV-2 positive test separated by at least a month. Our data suggest that additional studies are needed to determine if viral load, and/or recurrent infections in the month prior to MIS-C contribute to MIS-C risk. Medical and family history were not associated with MIS-C in our analysis.
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    Author Correction: Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C
    (Springer Nature, 2022-08-12) Tang, Juanjie; Novak, Tanya; Hecker, Julian; Grubbs, Gabrielle; Zahra, Fatema Tuz; Bellusci, Lorenza; Pourhashemi, Sara; Chou, Janet; Moffitt, Kristin; Halasa, Natasha B.; Schwartz, Stephanie P.; Walker, Tracie C.; Tarquinio, Keiko M.; Zinter, Matt S.; Staat, Mary A.; Gertz, Shira J.; Cvijanovich, Natalie Z.; Schuster, Jennifer E.; Loftis, Laura L.; Coates, Bria M.; Mack, Elizabeth H.; Irby, Katherine; Fitzgerald, Julie C.; Rowan, Courtney M.; Kong, Michele; Flori, Heidi R.; Maddux, Aline B.; Shein, Steven L.; Crandall, Hillary; Hume, Janet R.; Hobbs, Charlotte V.; Tremoulet, Adriana H.; Shimizu, Chisato; Burns, Jane C.; Chen, Sabrina R.; Moon, Hye Kyung; Lange, Christoph; Randolph, Adrienne G.; Khurana, Surender; Pediatrics, School of Medicine
    Correction to: Nature Communications 10.1038/s41467-022-30649-1, published online 27 May 2022
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    Cross-reactive immunity against the SARS-CoV-2 Omicron variant is low in pediatric patients with prior COVID-19 or MIS-C
    (Springer Nature, 2022-05-27) Tang, Juanjie; Novak, Tanya; Hecker, Julian; Grubbs, Gabrielle; Tuz Zahra, Fatema; Bellusci, Lorenza; Pourhashemi, Sara; Chou, Janet; Moffitt, Kristin; Halasa, Natasha B.; Schwartz, Stephanie P.; Walker, Tracie C.; Tarquinio, Keiko M.; Zinter, Matt S.; Staat, Mary A.; Gertz, Shira J.; Cvijanovich, Natalie Z.; Schuster, Jennifer E.; Loftis, Laura L.; Coates, Bria M.; Mack, Elizabeth H.; Irby, Katherine; Fitzgerald, Julie C.; Rowan, Courtney M.; Kong, Michele; Flori, Heidi R.; Maddux, Aline B.; Shein, Steven L.; Crandall, Hillary; Hume, Janet R.; Hobbs, Charlotte V.; Tremoulet, Adriana H.; Shimizu, Chisato; Burns, Jane C.; Chen, Sabrina R.; Moon, Hye Kyung; Lange, Christoph; Randolph, Adrienne G.; Khurana, Surender; Pediatrics, School of Medicine
    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.
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    Investigating Health Disparities Associated With Multisystem Inflammatory Syndrome in Children After SARS-CoV-2 Infection
    (Wolters Kluwer, 2022) Zambrano, Laura D.; Ly, Kathleen N.; Link-Gelles, Ruth; Newhams, Margaret M.; Akande, Manzilat; Wu, Michael J.; Feldstein, Leora R.; Tarquinio, Keiko M.; Sahni, Leila C.; Riggs, Becky J.; Singh, Aalok R.; Fitzgerald, Julie C.; Schuster, Jennifer E.; Giuliano, John S., Jr.; Englund, Janet A.; Hume, Janet R.; Hall, Mark W.; Osborne, Christina M.; Doymaz, Sule; Rowan, Courtney M.; Babbitt, Christopher J.; Clouser, Katharine N.; Horwitz, Steven M.; Chou, Janet; Patel, Manish M.; Hobbs, Charlotte; Randolph, Adrienne G.; Campbell, Angela P.; Overcoming COVID-19 Investigators; Pediatrics, School of Medicine
    Background: Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complication that has disproportionately affected racial/ethnic minority children. We conducted a pilot study to investigate risk factors for MIS-C aiming to understand MIS-C disparities. Methods: This case-control study included MIS-C cases and SARS-CoV-2-positive outpatient controls less than 18 years old frequency-matched 4:1 to cases by age group and site. Patients hospitalized with MIS-C were admitted between March 16 and October 2, 2020, across 17 pediatric hospitals. We evaluated race, ethnicity, social vulnerability index (SVI), insurance status, weight-for-age and underlying medical conditions as risk factors using mixed effects multivariable logistic regression. Results: We compared 241 MIS-C cases with 817 outpatient SARS-CoV-2-positive at-risk controls. Cases and controls had similar sex, age and U.S. census region distribution. MIS-C patients were more frequently previously healthy, non-Hispanic Black, residing in higher SVI areas, and in the 95th percentile or higher for weight-for-age. In the multivariable analysis, the likelihood of MIS-C was higher among non-Hispanic Black children [adjusted odds ratio (aOR): 2.07; 95% CI: 1.23-3.48]. Additionally, SVI in the 2nd and 3rd tertiles (aOR: 1.88; 95% CI: 1.18-2.97 and aOR: 2.03; 95% CI: 1.19-3.47, respectively) were independent factors along with being previously healthy (aOR: 1.64; 95% CI: 1.18-2.28). Conclusions: In this study, non-Hispanic Black children were more likely to develop MIS-C after adjustment for sociodemographic factors, underlying medical conditions, and weight-for-age. Investigation of the potential contribution of immunologic, environmental, and other factors is warranted.
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    NFKB2 haploinsufficiency identified via screening for IFN-α2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
    (Elsevier, 2023) Bodansky, Aaron; Vazquez, Sara E.; Chou, Janet; Novak, Tanya; Al-Musa, Amer; Young, Cameron; Newhams, Margaret; Kucukak, Suden; Zambrano, Laura D.; Mitchell, Anthea; Wang, Chung-Yu; Moffitt, Kristin; Halasa, Natasha B.; Loftis, Laura L.; Schwartz, Stephanie P.; Walker, Tracie C.; Mack, Elizabeth H.; Fitzgerald, Julie C.; Gertz, Shira J.; Rowan, Courtney M.; Irby, Katherine; Sanders, Ronald C., Jr.; Kong, Michele; Schuster, Jennifer E.; Staat, Mary A.; Zinter, Matt S.; Cvijanovich, Natalie Z.; Tarquinio, Keiko M.; Coates, Bria M.; Flori, Heidi R.; Dahmer, Mary K.; Crandall, Hillary; Cullimore, Melissa L.; Levy, Emily R.; Chatani, Brandon; Nofziger, Ryan; Overcoming COVID-19 Network Study Group Investigators; Geha, Raif S.; DeRisi, Joseph; Campbell, Angela P.; Anderson, Mark; Randolph, Adrienne G.; Pediatrics, School of Medicine
    Background: Autoantibodies against type I IFNs occur in approximately 10% of adults with life-threatening coronavirus disease 2019 (COVID-19). The frequency of anti-IFN autoantibodies in children with severe sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. Objective: We quantified anti-type I IFN autoantibodies in a multicenter cohort of children with severe COVID-19, multisystem inflammatory syndrome in children (MIS-C), and mild SARS-CoV-2 infections. Methods: Circulating anti-IFN-α2 antibodies were measured by a radioligand binding assay. Whole-exome sequencing, RNA sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFN-α2 autoantibodies exceeding the assay's positive control. Results: Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only 1 had high levels of anti-IFN-α2 antibodies. Anti-IFN-α2 autoantibodies were not detected in patients treated with intravenous immunoglobulin before sample collection. Whole-exome sequencing identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of nuclear factor kappa-light-chain enhancer of activated B cells, aka NF-κB, essential for noncanonical NF-κB signaling. The patient's peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. Conclusions: High levels of anti-IFN-α2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare but can occur in patients with inborn errors of immunity.
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    NFKB2 haploinsufficiency identified via screening for IFNα2 autoantibodies in children and adolescents hospitalized with SARS-CoV-2-related complications
    (Elsevier, 2023-04) Bodansky, Aaron; Vazquez, Sara E.; Chou, Janet; Novak, Tanya; Al-Musa, Amer; Young, Cameron; Newhams, Margaret; Kocukak, Suden; Zambrano, Laura D.; Mitchell, Anthea; Wang, Chung-Yu; Moffitt, Kristin; Halasa, Natasha B.; Loftis, Laura L.; Schwartz, Stephanie P.; Walker, Tracie C.; Mack, Elizabeth H.; Fitzgerald, Julie C.; Gertz, Shira J.; Rowan, Courtney M.; Irby, Katherine; Sanders, Ronald C., Jr.; Kong, Michele; Schuster, Jennifer E.; Staat, Mary A.; Zinter, Matt S.; Cvijanovich, Natalie Z.; Tarquinio, Keiko M.; Coates, Bria M.; Flori, Heidi R.; Dahmer, Mary K.; Crandall, Hillary; Cullimore, Melissa L.; Levy, Emily R.; Chatani, Brandon; Nofziger, Ryan; Overcoming COVID-19 Network Study Group Investigators; Geha, Raif S.; DeRisi, Joseph; Campbell, Angela P.; Anderson, Mark; Randolph, Adrienne G.; Pediatrics, School of Medicine
    Background Autoantibodies against type I interferons (IFNs) occur in approximately 10% of adults with life-threatening COVID-19. The frequency of anti-IFN autoantibodies in children with severe sequelae of SARS-CoV-2 infection is unknown. Objective To quantify anti-Type I IFN autoantibodies in a multi-center cohort of children with severe COVID-19, Multisystem Inflammatory Syndrome in Children (MIS-C), and mild SARS-CoV-2 infections. Methods Circulating anti-IFNa2 antibodies were measured by a radioligand binding assay. Whole exome sequencing (WES), RNA-sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFNα2 autoantibodies exceeding the assay’s positive control. Results Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only one had high levels of anti-IFNα2 antibodies. Anti-IFNα2 autoantibodies were not detected in patients treated with intravenous immunoglobulin prior to sample collection. WES identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of NF-kB essential for non-canonical NF-kB signaling. Her peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity. Conclusions High levels of anti-IFNα2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare, but can occur in patients with inborn errors of immunity. Clinical implications Anti-IFNα2 autoantibodies should prompt diagnostic evaluation for inborn errors of immunity if identified in children or adolescents.
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    Risk Factors for Multisystem Inflammatory Syndrome in Children: A Case-Control Investigation
    (Wolters Kluwer, 2023) Zambrano, Laura D.; Wu, Michael J.; Martin, Lora; Malloch, Lacy; Chen, Sabrina; Newhams, Margaret M.; Kucukak, Suden; Son, Mary Beth; Sanders, Cameron; Patterson, Kayla; Halasa, Natasha; Fitzgerald, Julie C.; Leroue, Matthew K.; Hall, Mark; Irby, Katherine; Rowan, Courtney M.; Wellnitz, Kari; Sahni, Leila C.; Loftis, Laura; Bradford, Tamara T.; Staat, Mary; Babbitt, Christopher; Carroll, Christopher L.; Pannaraj, Pia S.; Kong, Michele; Schuster, Jennifer E.; Chou, Janet; Patel, Manish M.; Randolph, Adrienne G.; Campbell, Angela P.; Hobbs, Charlotte V.; Overcoming COVID-19 investigators; Pediatrics, School of Medicine
    Background: In a 2020 pilot case-control study using medical records, we reported that non-Hispanic Black children were more likely to develop multisystem inflammatory syndrome in children (MIS-C) after adjustment for sociodemographic factors and underlying medical conditions. Using structured interviews, we investigated patient, household, and community factors underlying MIS-C likelihood. Methods: MIS-C case patients hospitalized in 2021 across 14 US pediatric hospitals were matched by age and site to outpatient controls testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the admission date. Caregiver interviews queried race/ethnicity, medical history, and household and potential community exposures 1 month before MIS-C hospitalization (case-patients) or after SARS-CoV-2 infection (controls). We calculated adjusted odds ratios (aOR) using mixed-effects multivariable logistic regression. Results: Among 275 case patients and 496 controls, race/ethnicity, social vulnerability and patient or family history of autoimmune/rheumatologic disease were not associated with MIS-C. In previously healthy children, MIS-C was associated with a history of hospitalization for an infection [aOR: 4.8; 95% confidence interval (CI): 2.1-11.0]. Household crowding (aOR: 1.7; 95% CI: 1.2-2.6), large event attendance (aOR: 1.7; 95% CI: 1.3-2.1), school attendance with limited masking (aOR: 2.6; 95% CI: 1.1-6.6), public transit use (aOR: 1.8; 95% CI: 1.4-2.4) and co-resident testing positive for SARS-CoV-2 (aOR: 2.2; 95% CI: 1.3-3.7) were associated with increased MIS-C likelihood, with risk increasing with the number of these factors. Conclusions: From caregiver interviews, we clarify household and community exposures associated with MIS-C; however, we did not confirm prior associations between sociodemographic factors and MIS-C.