Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Funding Information: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21-RHUS-08 (COVIFERON), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government's Investissement d'Avenir program, Laboratoires d'Excellence "Integrative Biology of Emerging Infectious Diseases" (ANR-10-LABX-62-IBEID) and "Milieu Intérieur" (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A. Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20-01333 and COV20-01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and "Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19"). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M.P, M.L.D., and J.P.-T. was funded by the European Commission-NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA. A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union's Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444; a George Mason University Fast Grant; the G. Harold and Leila Y. Mathers Charitable Foundation; the Meyer Foundation; and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). Publisher Copyright: © 2023 American Association for the Advancement of Science. All rights reserved.Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.publishersversionpublishe

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Rsv frequency, clinical symptoms and cost analysis of children < 2 years old hospitalized for lower respiratory tract infection in central Bursa

Prospektif ve çok merkezli bu çalışmada, Türkiye'de Bursa il merkezinde 0-2 yaş arası alt solunum yolu enfeksiyonu (ASYE) nedeniyle hastaneye yatırılan olgularda Respiratuvar Sinsityal Virüs (RSV) epidemiyolojik özellikleri, klinik özellikleri ve maliyet analizinin değerlendirilmesi amaçlandı. Çalışmada RSV+ ASYE sıklığı %37.9, RSV+ akut bronşiolit sıklığı %41.0, RSV+ pnömoni sıklığı %34.0 olarak bulundu. Bursa il merkezinde ≤2 yaş RSV+ ASYE, RSV+ akut bronşiolit ve RSV+ pnömoni nedeniyle yıllık yatış insidanslarımız sırasıyla 7.8/1000, 4.6/1000 ve 3.2/1000 olarak hesaplandı. Bu sonuçlar Türkiye'ye yansıtıldığında, bir yılda ≤2 yaşta yaklaşık 453 500 olgunun ASYE nedeniyle hastaneye yatması bekleneceği ve bunların da tahmini olarak 18 800'ünün RSV+ ASYE yatışı olduğu tahmini olarak hesaplandı. Çalışmamızda RSV+ ASYE nedeniyle yatan bir olgunun ortalama yatış direkt tıbbi maliyeti 1 652.2 TL, 910.1 $ve 721.0 € olarak hesaplandı. Toplam yatış maliyetleri tüm Türkiye bazında değerlendirildiğinde ise RSV+ ASYE nedeniyle yatış maliyetimizin yılda yaklaşık ortalama 419 658.8 TL, 231 178.7$ ve 183 137.1 € olması beklenmektedir. Bu sonuçlara göre RSV enfeksiyonları halen ülkemizde < 2 yaşta ASYE'lerin önemli bir kısmını oluşturmakta ve önemli bir epidemiyolojik ve ekonomik hastalık yüküne neden olmaktadır.In this prospective and multi-centric study, the objective was to evaluate the epidemiological properties, clinical features and cost analysis of Respiratory Syncytial Virus infection in children between 0-2 years hospitalized with lower respiratory tract infection (LRTI) in central Bursa in Turkey. In the study, the RSV+ LRTI frequency was found 37.9%, RSV+ acute bronchiolitis frequency was found 41.0% and RSV+ pneumonia frequency was found 34.0%. The incidences of RSV+ LRTI, RSV+ acute bronchiolitis and RSV+ pneumonia between 0-2 years in Bursa were found 7.8/1000, 4.6/1000 and 3.2/1000, respectively. When these results are projected to Turkey, 453 500 children between 0-2 years are expected to be hospitalized for LRTI and of these children 18 800 are expected to be hospitalized for RSV+ LRTI. In the study direct medical cost of a patient hospitalized for RSV+ LRTI was calculated as average 1 652.2 TL, 910.1 $and 721.0 €. When the total hospitalization direct medical costs are projected to Turkey, the direct medical costs of hospitalization of 0-2 years old children was calculated as 419 658.8 TL (231 178.7$ and 183 137.1 €). According to these results, RSV+ LRTIs causes a high epidemiologic and economic disease burden

Tularemia in children: Evaluation of clinical, laboratory and treatment outcomes of 15 tularemia cases Çocuklarda tularemi: Tularemili 15 olgunun klinik, laboratuvar ve tedavi sonuçlari{dotless}ni{dotless}n deǧerlendirilmesi

Introduction: Tularemia is a zoonotic diseases caused by Francisella tularensis. The aim of this study was to evaluate the clinical and laboratory findings of 15 children with the diagnosis of tularemia. Materials and Methods: Fifteen cases admitted with fever, sore throat, lymphadenopathy and a F. tularensis antibody titer of 1/160 and above in the microagglutination test (MAT) were evaluated retrospectively. Their sociodemographic characteristics, contact with animals, history of tick bite, duration of complaints, clinical and laboratory findings, treatments and clinical courses were studied. Results: The mean age of patients was 11.5±5.1 (3-17) years and 61.3% were male. Fiftythree percent of the patients were living in rural areas, and had contact with contaminated water. Swelling in the neck (93.3%), sore throat (66.7%) and fever (66.7%) were the most frequently observed symptoms. Oropharyngeal tularemia (66.7%) was predominated. In 27% of the patients LAPs were drained surgically, and in 13.3% of cases they were drained by itself. The mean duration between onset of tularemia symptoms and diagnosis was 53±45.3 (5150) days. Sixty percent of patients were received beta-lactam-antibiotics before admission. It was noted that 6 patients with suppurative lymph nodes were admitted to hospital within median 61 (20-150) days, while others were admitted within median 35 (5-75) days (p<0.05). Mean leukocyte count was 8558.6±1384.5 (6030-11400)/mm3, mean CRP was 5.8±2.9 (1-6.7) mg/dl, and mean ESR was 33.1±28.9 (6-103) mm/h. MAT showed that titers ranged from 1/160 to 1/1280. Gentamicin was given in seven patients (47%), streptomycin in five patients (33%), and doxycycline in 3 patients (20%). Conclusions: Tularemia should to be taken into account in the differential diagnosis in patients having tonsillopharyngitis and cervical lymphadenopathy without response to beta-lactam antibiotics in rural areas. © The Journal of Current Pediatrics, published by Galenos Publishing