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1. Hemostasis Proteins in Invasive Meningococcal and Nonmeningococcal Infections

Author

Hagedoorn, NN, Boeddha, NP, Kohlfuerst, DS, Anderson, S, Carrol, ED, Agapow, P, Van der Flier, M, Hazelzet, J, Herberg, J, Kuijpers, T, Levin, M, Martinon-Torres, F, Van Rijswijk, A, Schlapbach, LJ, Vermont, C, Zenz, W, Dik, WA, Driessen, G, Emonts, M, EUCLIDS Consortium, European Commission, MUMC+: MA Kindergeneeskunde (3), Kindergeneeskunde, RS: GROW - R4 - Reproductive and Perinatal Medicine, Pediatrics, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Infectious diseases, ARD - Amsterdam Reproduction and Development, Public Health, and Immunology

Subjects
Staphylococcus aureus, Thrombomodulin, European Union Childhood Life-threatening Infectious Disease (EUCLIDS) Consortium, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], ADAMTS13 Protein, 1110 Nursing, Neisseria meningitidis, Critical Care and Intensive Care Medicine, Pediatrics, Hemostatics, children, Sepsis, Humans, Prospective Studies, coagulation, Child, intensive care, Hemostasis, bacterial infection, Bacterial Infections, mortality, Fibronectins, Meningococcal Infections, hemostasis proteins, Pediatrics, Perinatology and Child Health, 1114 Paediatrics and Reproductive Medicine
Abstract

Contains fulltext : 287940.pdf (Publisher’s version ) (Open Access) OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.

Published
2022
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2. Guideline adherence in febrile children below 3 months visiting European Emergency Departments

Author

Tan, C.D., Walle, E.E.P.L. van der, Vermont, C.L., Both, U. von, Carrol, E.D., Eleftheriou, I., Emonts, M., Flier, M. van der, Groot, R. de, Herberg, J., Kohlmaier, B., Levin, M., Lim, E., Maconochie, I.K., Martinon-Torres, F., Nijman, R.G., Pokorn, M., Rivero-Calle, I., Tsolia, M., Yeung, S., Zenz, W., Zavadska, D., Neeleman, C., Gool, A.J. van, Gloerich, J., Huijnen, M.A., Moll, H.A., Pediatrics, Internal Medicine, Radiation Oncology, AII - Infectious diseases, Amsterdam Reproduction & Development (AR&D), European Commission, National Institute of Health and Medical Research, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Landsteiner Laboratory, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, AII - Inflammatory diseases, Paediatrics, Graduate School, University of Zurich, and Union), PERFORM consortium (Personalised Risk assessment in febrile children to optimize Real-life Management across the European

Subjects
Fever, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], INFANTS, 610 Medicine & health, Guideline, Pediatrics, 1117 Public Health and Health Services, Humans, Child, Children, Science & Technology, PERFORM consortium (Personalised Risk assessment in febrile children to optimize Real-life Management across the European Union), Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SERIOUS BACTERIAL-INFECTIONS, Bacterial Infections, 10027 Clinic for Neonatology, Anti-Bacterial Agents, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Pediatrics, Perinatology and Child Health, 1114 Paediatrics and Reproductive Medicine, Emergency care, Guideline Adherence, Emergency Service, Hospital, Life Sciences & Biomedicine, Biomarkers
Abstract

Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0–18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0–2.3). Management per ED varied as follows: use of diagnostic tests 14–83%, antibiotic treatment 23–54%, admission 34–86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0–38%), partial adherence occurred in 56% (484/868, range 35–77%).Conclusion: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. What is Known:• Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment.• There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence. What is New:• Full guideline adherence is limited, whereas partial guideline adherence is moderate in febrile children below 3 months across Europe.• Guideline revision including new biomarkers is needed to improve management in young febrile children.

Published
2022
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3. Treatment of Multisystem Inflammatory Syndrome in Children

Author

McArdle A. J., Vito O., Patel H., Seaby E. G., Shah P., Wilson C., Broderick C., Nijman R., Tremoulet A. H., Munblit D., Ulloa-Gutierrez R., Carter M. J., De T., Hoggart C., Whittaker E., Herberg J. A., Kaforou M., Cunnington A. J., Levin M., Vazquez J. A., Carmona R., Perez L., Rubinos M., Veliz N., Yori S., Haerynck F., Hoste L., Leal I. A., Da Silva A. R. A., Silva A. E. A., Barchik A., Barreiro S. T. A., Cochrane N., Teixeira C. H., Arauj J. M., Ossa R. A. P. -D. L., Vieira C. S., Dimitrova A., Ganeva M., Stefanov S., Telcharova-Mihaylovska A., Biggs C. M., Scuccimarri R., Withington D., Raul B. B., Ampuero C., Aravena J., Casanova D., Cruces P., Diaz F., Garcia-Salum T., Godoy L., Medina R. A., Galaz G. V., Avila-Aguero M. L., Brenes-Chacon H., Ivankovich-Escoto G., Yock-Corrales A., Badib A., Badreldin K., Elkhashab Y., Heshmat H., Heinonen S., Angoulvant F., Belot A., Ouldali N., Beske F., Heep A., Masjosthusmann K., Reiter K., Heuvel I. V. D., Both U. V., Agrafiotou A., Antachopoulos C., Eleftheriou I., Farmaki E., Fotis L., Kafetzis D., Lampidi S., Liakopoulou T., Maritsi D., Michailidou E., Milioudi M., Mparmpounaki I., Papadimitriou E., Papaevangelou V., Roilides E., Tsiatsiou O., Tsolas G., Tsolia M., Vantsi P., Pineda L. Y. B., Aguilar K. L. B., Quintero E. M. C., Ip P., Kwan M. Y. W., Kwok J., Lau Y. L., To K., Wong J. S. C., David M., Farkas D., Kalcakosz S., Szekeres K., Zsigmond B., Aslam N., Andreozzi L., Bianco F., Bucciarelli V., Buonsenso D., Cimaz R., D'Argenio P., Dellepiane R. M., Fabi M., Mastrolia M. V., Mauro A., Mazza A., Romani L., Simonini G., Tipo V., Valentini P., Verdoni L., Reel B., Pace D., Torpiano P., Flores M. F., Dominguez M. G., Vargas A. L. G., Hernandez L. L., Figueroa R. P. M., Gaxiola G. P., Valadez J., Klevberg S., Knudsen P. K., Maseide P. H., Carrera J. M., Castano E. G., Timana C. A. D., Leon T. D., Estripeaut D., Levy J., Norero X., Record J., Rojas-Bonilla M., Iramain R., Hernandez R., Huaman G., Munaico M., Peralta C., Seminario D., Yarleque E. H. Z., Gadzinska J., Mandziuk J., Okarska-Napierala M., Alacheva Z. A., Alexeeva E., Ananin P. V., Antsupova M., Bakradze M. D., Bobkova P., Borzakova S., Chashchina I. L., Fisenko A. P., Gautier M. S., Glazyrina A., Kondrikova E., Korobyants E., Korsunskiy A. A., Kovygina K., Krasnaya E., Kurbanova S., Kurdup M. K., Mamutova A. V., Mazankova L., Mitushin I. L., Nargizyan A., Orlova Y. O., Osmanov I. M., Polyakova A. S., Romanova O., Samitova E., Sologub A., Spiridonova E., Tepaev R. F., Tkacheva A. A., Yusupova V., Zholobova E., Grasa C. D., Segura N. L., Martinon-Torres F., Melendo S., Echevarria A. M., Guzman J. M. M., Argueta J. R. P., Rivero-Calle I., Riviere J., Rodriguez-Gonzalez M., Rojo P., Manubens J. S., Soler-Palacin P., Soriano-Arandes A., Tagarro A., Villaverde S., Altman M., Brodin P., Horne A., Palmblad K., Brotschi B., Sauteur P. M., Schmid J. P., Prader S., Relly C., Schlapbach L. J., Seiler M., Truck J., Wutz D., Ketharanathan N., Vermont C., Ozkan E. A., Erdeniz E. H., Borisova G., Boychenko L., Diudenko N., Kasiyan O., Katerynych K., Melnyk K., Miagka N., Teslenko M., Trykosh M., Volokha A., Akomolafe T., Al-Abadi E., Alders N., Avram P., Bamford A., Bank M., Roy R. B., Beattie T., Boleti O., Broad J., Carrol E. D., Chandran A., Cooper H., Davies P., Emonts M., Evans C., Fidler K., Foster C., Gong C., Gongrun B., Gonzalez C., Grandjean L., Grant K., Hacohen Y., Hall J., Hassell J., Hesketh C., Hewlett J., Hnieno A., Holt-Davis H., Hossain A., Hudson L. D., Johnson M., Johnson S., Jyothish D., Kampmann B., Kavirayani A., Kelly D., Kucera F., Langer D., Lillie J., Longbottom K., Lyall H., MacKdermott N., Maltby S., McLelland T., McMahon A. -M., Miller D., Morrison Z., Mosha K., Muller J., Myttaraki E., Nadel S., Osaghae D., Osman F., Ostrzewska A., Panthula M., Papachatzi E., Papadopoulou C., Penner J., Polandi S., Prendergast A. J., Ramnarayan P., Rhys-Evans S., Riordan A., Rodrigues C. M. C., Romaine S., Seddon J., Shingadia D., Srivastava A., Struik S., Taylor A., Tran S., Tudor-Williams G., Van Der Velden F., Ventilacion L., Wellman P. A., Yanney M. P., Yeung S., Badheka A., Badran S., Bailey D. M., Burch A. K., Burns J. C., Cichon C., Cirks B., Dallman M. D., Delany D. R., Fairchok M., Friedman S., Geracht J., Langs-Barlow A., Mann K., Padhye A., Quade A., Ramirez K. A., Rockett J., Sayed I. A., Shahin A. A., Umaru S., Widener R., Angela M. H., Kandawasvika G., McArdle A.J., Vito O., Patel H., Seaby E.G., Shah P., Wilson C., Broderick C., Nijman R., Tremoulet A.H., Munblit D., Ulloa-Gutierrez R., Carter M.J., De T., Hoggart C., Whittaker E., Herberg J.A., Kaforou M., Cunnington A.J., Levin M., Vazquez J.A., Carmona R., Perez L., Rubinos M., Veliz N., Yori S., Haerynck F., Hoste L., Leal I.A., Da Silva A.R.A., Silva A.E.A., Barchik A., Barreiro S.T.A., Cochrane N., Teixeira C.H., Arauj J.M., Ossa R.A.P.-D.L., Vieira C.S., Dimitrova A., Ganeva M., Stefanov S., Telcharova-Mihaylovska A., Biggs C.M., Scuccimarri R., Withington D., Raul B.B., Ampuero C., Aravena J., Casanova D., Cruces P., Diaz F., Garcia-Salum T., Godoy L., Medina R.A., Galaz G.V., Avila-Aguero M.L., Brenes-Chacon H., Ivankovich-Escoto G., Yock-Corrales A., Badib A., Badreldin K., Elkhashab Y., Heshmat H., Heinonen S., Angoulvant F., Belot A., Ouldali N., Beske F., Heep A., Masjosthusmann K., Reiter K., Heuvel I.V.D., Both U.V., Agrafiotou A., Antachopoulos C., Eleftheriou I., Farmaki E., Fotis L., Kafetzis D., Lampidi S., Liakopoulou T., Maritsi D., Michailidou E., Milioudi M., Mparmpounaki I., Papadimitriou E., Papaevangelou V., Roilides E., Tsiatsiou O., Tsolas G., Tsolia M., Vantsi P., Pineda L.Y.B., Aguilar K.L.B., Quintero E.M.C., Ip P., Kwan M.Y.W., Kwok J., Lau Y.L., To K., Wong J.S.C., David M., Farkas D., Kalcakosz S., Szekeres K., Zsigmond B., Aslam N., Andreozzi L., Bianco F., Bucciarelli V., Buonsenso D., Cimaz R., D'Argenio P., Dellepiane R.M., Fabi M., Mastrolia M.V., Mauro A., Mazza A., Romani L., Simonini G., Tipo V., Valentini P., Verdoni L., Reel B., Pace D., Torpiano P., Flores M.F., Dominguez M.G., Vargas A.L.G., Hernandez L.L., Figueroa R.P.M., Gaxiola G.P., Valadez J., Klevberg S., Knudsen P.K., Maseide P.H., Carrera J.M., Castano E.G., Timana C.A.D., Leon T.D., Estripeaut D., Levy J., Norero X., Record J., Rojas-Bonilla M., Iramain R., Hernandez R., Huaman G., Munaico M., Peralta C., Seminario D., Yarleque E.H.Z., Gadzinska J., Mandziuk J., Okarska-Napierala M., Alacheva Z.A., Alexeeva E., Ananin P.V., Antsupova M., Bakradze M.D., Bobkova P., Borzakova S., Chashchina I.L., Fisenko A.P., Gautier M.S., Glazyrina A., Kondrikova E., Korobyants E., Korsunskiy A.A., Kovygina K., Krasnaya E., Kurbanova S., Kurdup M.K., Mamutova A.V., Mazankova L., Mitushin I.L., Nargizyan A., Orlova Y.O., Osmanov I.M., Polyakova A.S., Romanova O., Samitova E., Sologub A., Spiridonova E., Tepaev R.F., Tkacheva A.A., Yusupova V., Zholobova E., Grasa C.D., Segura N.L., Martinon-Torres F., Melendo S., Echevarria A.M., Guzman J.M.M., Argueta J.R.P., Rivero-Calle I., Riviere J., Rodriguez-Gonzalez M., Rojo P., Manubens J.S., Soler-Palacin P., Soriano-Arandes A., Tagarro A., Villaverde S., Altman M., Brodin P., Horne A., Palmblad K., Brotschi B., Sauteur P.M., Schmid J.P., Prader S., Relly C., Schlapbach L.J., Seiler M., Truck J., Wutz D., Ketharanathan N., Vermont C., Ozkan E.A., Erdeniz E.H., Borisova G., Boychenko L., Diudenko N., Kasiyan O., Katerynych K., Melnyk K., Miagka N., Teslenko M., Trykosh M., Volokha A., Akomolafe T., Al-Abadi E., Alders N., Avram P., Bamford A., Bank M., Roy R.B., Beattie T., Boleti O., Broad J., Carrol E.D., Chandran A., Cooper H., Davies P., Emonts M., Evans C., Fidler K., Foster C., Gong C., Gongrun B., Gonzalez C., Grandjean L., Grant K., Hacohen Y., Hall J., Hassell J., Hesketh C., Hewlett J., Hnieno A., Holt-Davis H., Hossain A., Hudson L.D., Johnson M., Johnson S., Jyothish D., Kampmann B., Kavirayani A., Kelly D., Kucera F., Langer D., Lillie J., Longbottom K., Lyall H., MacKdermott N., Maltby S., McLelland T., McMahon A.-M., Miller D., Morrison Z., Mosha K., Muller J., Myttaraki E., Nadel S., Osaghae D., Osman F., Ostrzewska A., Panthula M., Papachatzi E., Papadopoulou C., Penner J., Polandi S., Prendergast A.J., Ramnarayan P., Rhys-Evans S., Riordan A., Rodrigues C.M.C., Romaine S., Seddon J., Shingadia D., Srivastava A., Struik S., Taylor A., Tran S., Tudor-Williams G., Van Der Velden F., Ventilacion L., Wellman P.A., Yanney M.P., Yeung S., Badheka A., Badran S., Bailey D.M., Burch A.K., Burns J.C., Cichon C., Cirks B., Dallman M.D., Delany D.R., Fairchok M., Friedman S., Geracht J., Langs-Barlow A., Mann K., Padhye A., Quade A., Ramirez K.A., Rockett J., Sayed I.A., Shahin A.A., Umaru S., Widener R., Angela M.H., Kandawasvika G., Pediatric Surgery, Pediatrics, University of Zurich, National Institute of Health and Medical Research, Wellcome Trust, Medical Research Foundation, Shah, Priyen [0000-0001-9164-8862], Ulloa-Gutierrez, Rolando [0000-0002-9157-9227], Herberg, Jethro A [0000-0001-6941-6491], Cunnington, Aubrey J [0000-0002-1305-3529], Levin, Michael [0000-0003-2767-6919], and Apollo - University of Cambridge Repository

Subjects
Inotrope, Male, medicine.medical_treatment, 2700 General Medicine, 030204 cardiovascular system & hematology, Antibodies, Viral, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Glucocorticoid, hemic and lymphatic diseases, Medicine and Health Sciences, 030212 general & internal medicine, Viral, Child, 11 Medical and Health Sciences, OUTCOMES, Respiration, Immunoglobulins, Intravenous, General Medicine, Systemic Inflammatory Response Syndrome, 3. Good health, Hospitalization, Treatment Outcome, Child, Preschool, Combination, Artificial, Regression Analysis, Drug Therapy, Combination, Female, Original Article, Intravenous, Life Sciences & Biomedicine, Cohort study, Human, medicine.medical_specialty, BATS Consortium, Adolescent, Immunoglobulins, 610 Medicine & health, Regression Analysi, Antibodies, Immunomodulation, 03 medical and health sciences, Medicine, General & Internal, Pharmacotherapy, Drug Therapy, Clinical Research, Internal medicine, General & Internal Medicine, medicine, MANAGEMENT, Confidence Intervals, Humans, Preschool, Propensity Score, Glucocorticoids, Mechanical ventilation, Science & Technology, business.industry, SARS-CoV-2, Inflammatory and immune system, COVID-19, Odds ratio, medicine.disease, Respiration, Artificial, Confidence interval, KAWASAKI-LIKE DISEASE, COVID-19 Drug Treatment, Systemic inflammatory response syndrome, 10036 Medical Clinic, Immunoglobulins, Intravenou, Propensity score matching, Cohort Studie, business, ACUTE RESPIRATORY SYNDROME, Confidence Interval, TOXIC-SHOCK-SYNDROME
Abstract

BackgroundEvidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.MethodsWe performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.ResultsData were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.ConclusionsWe found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).

Published
2021

4. Rapid Viral Testing and Antibiotic Prescription in Febrile Children With Respiratory Symptoms Visiting Emergency Departments in Europe

Author

Tan, C.D., Hagedoorn, N.N., Dewez, J.E., Borensztajn, D.M., Both, U. von, Carrol, E.D., Emonts, M., Flier, M. van der, Groot, R. de, Herberg, J., Kohlmaier, B., Levin, M., Lim, E., Maconochie, I.K., Martinon-Torres, F., Nijman, R.G., Pokorn, M., Rivero-Calle, I., Strle, F., Tsolia, M., Vermont, C.L., Yeung, S., Zachariasse, J.M., Zenz, W., Gool, A.J. van, Gloerich, J., Zavadska, D., Moll, H.A., and Pediatrics

Subjects
Microbiology (medical), Male, medicine.medical_specialty, Adolescent, Fever, medicine.drug_class, Antibiotics, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Inappropriate Prescribing, Logistic regression, Antibiotic resistance, SDG 3 - Good Health and Well-being, Internal medicine, Medicine, Humans, Respiratory system, Child, Respiratory Tract Infections, Respiratory tract infections, medicine.diagnostic_test, business.industry, Infant, Newborn, Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Emergency department, Anti-Bacterial Agents, Europe, Infectious Diseases, Prescriptions, Virus Diseases, Child, Preschool, Pediatrics, Perinatology and Child Health, Observational study, Female, business, Chest radiograph, Emergency Service, Hospital
Abstract

Contains fulltext : 248225.pdf (Publisher’s version ) (Closed access) BACKGROUND: Inappropriate antibiotic prescribing often occurs in children with self-limiting respiratory tract infections, contributing to antimicrobial resistance. It has been suggested that rapid viral testing can reduce inappropriate antibiotic prescribing. We aimed to assess the association between rapid viral testing at the Emergency Department (ED) and antibiotic prescription in febrile children. METHODS: This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0-18 years) attending 12 European EDs. In children with respiratory symptoms visiting 6 EDs equipped with rapid viral testing, we performed multivariable logistic regression analysis regarding rapid viral testing and antibiotic prescription adjusted for patient characteristics, disease severity, diagnostic tests, focus of infection, admission, and ED. RESULTS: A rapid viral test was performed in 1061 children (8%) and not performed in 11,463 children. Rapid viral test usage was not associated with antibiotic prescription (aOR 0.9, 95% CI: 0.8-1.1). A positive rapid viral test was associated with less antibiotic prescription compared with children without test performed (aOR 0.6, 95% CI: 0.5-0.8), which remained significant after adjustment for CRP and chest radiograph result. Twenty percent of the positively tested children received antibiotics. A negative rapid viral test was not associated with antibiotic prescription (aOR 1.2, 95% CI: 1.0-1.4). CONCLUSIONS: Rapid viral test usage did not reduce overall antibiotic prescription, whereas a positive rapid viral test did reduce antibiotic prescription at the ED. Implementation of rapid viral testing in routine emergency care and compliance to the rapid viral test outcome will reduce inappropriate antibiotic prescribing at the ED.

Published
2022

5. Sex differences in febrile children with respiratory symptoms attending European emergency departments: An observational multicenter study

Author

Tan, C.D., Ouasghiri, S. El, Both, U. von, Carrol, E.D., Emonts, M., Flier, M. van der, Groot, R. de, Herberg, J., Kohlmaier, B., Levin, M., Lim, E., Maconochie, I.K., Martinon-Torres, F., Nijman, R.G., Pokorn, M., Rivero-Calle, I., Tsolia, M., Vermont, C.L., Zenz, W., Zavadska, D., Gool, A.J. van, Gloerich, J., Moll, H.A., Zachariasse, J.M., Pediatrics, Erasmus MC other, and European Commission

Subjects
Male, Sex Characteristics, Multidisciplinary, Fever, General Science & Technology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Infant, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Urinary Tract Infections, Humans, PERFORM consortium (Personalised Risk assessment in febrile children to optimise Real-life Management across the European Union), Female, Child, Emergency Service, Hospital, Respiratory Tract Infections
Abstract

Objective To assess sex differences in presentation and management of febrile children with respiratory symptoms attending European Emergency Departments. Design and setting An observational study in twelve Emergency Departments in eight European countries. Patients Previously healthy children aged 0– Main outcome measures The main outcomes were patient characteristics and management defined as diagnostic tests, treatment and admission. Descriptive statistics were used for patient characteristics and management stratified by sex. Multivariable logistic regression analyses were performed for the association between sex and management with adjustment for age, disease severity and Emergency Department. Additionally, subgroup analyses were performed in children with upper and lower respiratory tract infections and in children below five years. Results We included 19,781 febrile children with respiratory symptoms. The majority were boys (54%), aged 1–5 years (58%) and triaged as low urgent (67%). Girls presented less frequently with tachypnea (15% vs 16%, p = 0.002) and increased work of breathing (8% vs 12%, p Conclusions Sex differences concerning presentation and management are present in previously healthy febrile children with respiratory symptoms presenting to the Emergency Department. Future research should focus on whether these differences are related to clinicians’ attitudes, differences in clinical symptoms at the time of presentation and disease severity.

Published
2022

6. Distinct patterns of within-host virus populations between two subgroups of human respiratory syncytial virus

Author

Lin, G. -L., Drysdale, S. B., Snape, M. D., O'Connor, D., Brown, A., MacIntyre-Cockett, G., Mellado-Gomez, E., de Cesare, M., Bonsall, D., Ansari, M. A., Oner, D., Aerssens, J., Butler, C., Bont, L., Openshaw, P., Martinon-Torres, F., Nair, H., Bowden, R., Campbell, H., Cunningham, S., Bogaert, D., Beutels, P., Wildenbeest, J., Clutterbuck, E., Mcginley, J., Thwaites, R., Wiseman, D., Gomez-Carballa, A., Rodriguez-Tenreiro, C., Rivero-Calle, I., Dacosta-Urbieta, A., Heikkinen, T., Meijer, A., Fischer, T. K., van den Berge, M., Giaquinto, C., Abram, M., Dormitzer, P., Stoszek, S., Gallichan, S., Rosen, B., Molero, E., Machin, N., Spadetto, M., Golubchik, T., Pollard, A. J., Investigators, RESCEU, and Commission of the European Communities

Subjects
Male, viruses, DIVERSITY, PROTEIN, General Physics and Astronomy, Virus Replication, INFECTION, Multidisciplinary, RSV, virus diseases, respiratory system, Antigenic Variation, Multidisciplinary Sciences, ALIGNMENT, Viral evolution, Monoclonal, Science & Technology - Other Topics, Female, Viral genetics, medicine.drug, Human, Palivizumab, Science, Mutation, Missense, PALIVIZUMAB, Respiratory Syncytial Virus Infections, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Virus, Viral Proteins, Antigen, Lower respiratory tract infection, Antigenic variation, medicine, Humans, Aged, Science & Technology, Genetic Variation, Infant, Respiratory Syncytial Virus, Human, General Chemistry, Vaccine efficacy, medicine.disease, PREVENTION, Virology, EVOLUTION, Viral infection, ANTIBODIES, Mutation, RESCEU Investigators, Respiratory Syncytial Virus, Missense, human activities, RESISTANCE
Abstract

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017–2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups., Respiratory syncytial virus (RSV) is a common infection in children and older adults but little is known about within-host viral population diversity. Here, the authors perform deep sequencing and find that RSV subgroup B exhibited more diversity than subgroup A, with implications for development of therapeutics and vaccines.

Published
2021

7. Infections, antibiotic treatment and mortality in patients admitted to ICUs in countries considered to have high levels of antibiotic resistance compared to those with low levels

Author

Michalopoulos, A., Groeneveld, J., Lev, A., Sprung, C., Vakalos, A., Kotanidou, A., Zakynthinos, E., Filos, K., Pneumatikos, I., Moraiti, A., Clouva-molyvdas, P., Mandragos, K., Kyriazopoulos, G., Karampela, I., Koulenti, D., Myrianthefs, P., Ioannidou, E., Mouloudi, E., Chalkiadaki, A., Bitzani, M., Routsi, C., Armaganidis, A., Sofianos, E., Harjola, V., Berezowicz, P., Jacobsen, K., Espersen, K., Fogh, B., Betsch, H., Vincent, Jean-Louis, Vanhems, Philippe, Walther, Sten M., Sakr, Yasser, Rello, Jordi, Leone, Marc, Pickkers, P., Lipman, Jeffrey, Holmbom, Martin, Antonelli, Massimo, Hanberger, Håkan, Kocak, S., Ulger, F., Guven, H., Turkmen, A., Dogruer, K., Adanir, T., Demirkiran, O., Tugrul, S., Cakar, N., Akinci, I., Uzel, N., Togal, T., Topeli, A., Turkoglu, M., Guven, M., Akan, M., Bodur, H., Bosnak, M., Kizilkaya, M., Ozgencil, E., Kaya, A., Fistikci, H., Ates, C., Atalan, K., Jacobson, S., Owall, A., Kokinsky, E., Rudenstam, J., Häggqvist, J., Hulting, J., Sellgren, J., Arvidsson, S., Schindele, M., Hammarskjöld, F., Friberg, H., Petersson, J., Paulsson, A., Lindström, I., Stiernstrom, H., Peterzén, B., Blomqvist, H., Petersen, P., Soto Ibáñez, J., González, J., Izura, J., Corcobado Márquez, C., Rico-Feijoo, J., Sierra, R., Rello, J., Posada, P., Briones Lopez, M., Jara, R., Luis, V., Maria Jesus, H., de la Torre-Prados, M., Felices, F., Sanchez Garcia, M., Macias Pingarrón, J., Garcia-Fuentes, C., Cerdá, E., Serrano, N., Barcenilla-Gaite, F., Sirvent, J., Montejo González, J., Guerrero Gomez, F., Amador Amerigo, J., Borges, M., Sánchez-Olmedo, J., López Ciudad, V., Moreno, M., Esteban, E., Vallés, J., De Rojas Román, J., Yuste, I., Ugarte Peña, P., Sole-violán, J., Bustinza, A., Albaya, A., Latour-Perez, J., Navarro, J., Garcia, F., Martin Delgado, M., Rovira, A., Ramos-gómez, L., Garro, P., Silva, J., Iglesias, L., María Jesús, L., Pueyo, L., Lorente, C., Martinon-Torres, F., Aguilar, G., Martinez-Sagasti, F., Blesa Malpica, A., Valencia, M., Zavala, E., Bustamante Munguira, E., Arribas, M., Insausti, J., Vegas Pinto, R., Bocero, L., Estella, A., Esteban-Reboll, F., Lopez Camps, V., Antón Caraballo, E., Muñoz, E., Olaechea, P., Escriba, A., Santos, I., Campiñez, Burgueño., Moreira, P., Pizzamiglio, M., Conti, V., Kahveci, A., Nydahl, A., Lind, D., Caballero Zirena, A., Guerrero, F., Palomar, M., Einar, V., Agvald-Ohman, C., Wyon, N., Johansson, L., Gil, B., Mariscal, F., Galvan, B., Espinosa, E., Lesmes Serrano, A., Mesalles Sanjuan, E., Manzano Ramirez, A., Quintana Tort-Martorell, E., Monton Dito, J., Ibañez, A., Garcia del Valle, S., Alemparte-Pardavila, E., Monedero, P., Naveira-Abeigón, E., Jorda, R., Alvarez, M., Rubio, O., Bouw, M., Afonso, Susana, Matos, Ricardo, Carneiro, A., Amaro, P., Ribeiro, R., Paiva, J., Galdos-Anuncibay, P., Nieto, M., Ruiz, J., Perez Calvo, C., Mañez, R., França, C., Moreno, R., Dias, C., Sousa, A., Rezende, A., Mourão, L., Ponce, P., Oliveira, T., Esteves, F., Den Boer, S., Bakker, J., Van Berkel, G., Borg, M., Gullo, A., Gianesello, L., Martinelli, L., Antonelli, M., Bassetti, M., Telo, L., Alves, M., Almeida, E., Leite, A., Pádua, F., Costa, H., Póvoa, P., Lopes, V., Carmo, E., Febra, C., Martins, A., Castelo-Branco Sousa, M., Bártolo, A., Junker, A., Erno, P., Klepstad, P., Loevstad, R., Bergmans, D., Rodgers, M., Pham, C., Speelberg, B., Wesselink, R., Ammann, J., Vet, J., Gille, A., Kuiper, M., Kieft, H., Blom, H., Vogelaar, J., Corsten, S., Ten Cate, J., Rosseel, P., De Pont, A., Della Rocca, G., Biancofiore, G., Morelli, A., Ranieri, MV., Cotogni, P., Alessandro, D., Clementi, S., Ferraro, F., Giuseppe, N., Sforza, D., Castiglione, G., Marino, G., Fumagalli, R., Santagostino, G., De Negri, P., De Gasperi, A., Oggioni, R., Conte, V., Sicignano, A., Marri, I., Locicero, M., Guadagnucci, A., Chieregato, A., Fiore, G., Sorbara, C., Munch, C., Ruatti, H., Lorella, P., Borrelli, F., Panella, L., De Blasi, R., Ceriani, R., Colonna, S., Abbruzzese, C., Rosano, A., Caspani, M., Emmi, V., Stelian, E., Scolz, S., Guberti, A., Margarit, O., Giarratano, A., Rosi, R., Marzorati, S., De blasio, E., Minerva, M., Petrucci, N., Mangani, V., Lazzero, A., Sapuppo, M., Cecilia, P., Borelli, M., Greco, S., Vesconi, S., Sofer, S., Cohen, J., Kishinevsky, E., Selçuk Üniversitesi, Hanberger, H, Antonelli, M, Holmbom, M, Lipman, J, Pickkers, P, Leone, M, Rello, J, Sakr, Y, Walther, S, Vanhems, P, Vincent, J, Betsch, H, Fogh, B, Espersen, K, Jacobsen, K, Berezowicz, P, Harjola, V, Sofianos, E, Armaganidis, A, Routsi, C, Bitzani, M, Chalkiadaki, A, Michalopoulos, A, Mouloudi, E, Ioannidou, E, Myrianthefs, P, Koulenti, D, Karampela, I, Kyriazopoulos, G, Mandragos, K, Clouva molyvdas, P, Moraiti, A, Pneumatikos, I, Filos, K, Zakynthinos, E, Kotanidou, A, Vakalos, A, Sprung, C, Lev, A, Kishinevsky, E, Cohen, J, Sofer, S, Vesconi, S, Greco, S, Borelli, M, Cecilia, P, Sapuppo, M, Lazzero, A, Mangani, V, Petrucci, N, Minerva, M, De blasio, E, Marzorati, S, Rosi, R, Giarratano, A, Margarit, O, Guberti, A, Scolz, S, Stelian, E, Emmi, V, Caspani, M, Rosano, A, Abbruzzese, C, Colonna, S, Ceriani, R, De Blasi, R, Panella, L, Borrelli, F, Lorella, P, Ruatti, H, Munch, C, Sorbara, C, Fiore, G, Chieregato, A, Conti, V, Guadagnucci, A, Pizzamiglio, M, Locicero, M, Marri, I, Sicignano, A, Conte, V, Oggioni, R, De Gasperi, A, De Negri, P, Santagostino, G, Fumagalli, R, Marino, G, Castiglione, G, Sforza, D, Giuseppe, N, Bassetti, M, Ferraro, F, Clementi, S, Alessandro, D, Cotogni, P, Ranieri, M, Martinelli, L, Gianesello, L, Gullo, A, Morelli, A, Biancofiore, G, Della Rocca, G, Borg, M, De Pont, A, Rosseel, P, Ten Cate, J, Van Berkel, G, Corsten, S, Bakker, J, Vogelaar, J, Blom, H, Kieft, H, Kuiper, M, Gille, A, Vet, J, Ammann, J, Den Boer, S, Wesselink, R, Speelberg, B, Pham, C, Rodgers, M, Bergmans, D, Groeneveld, J, Loevstad, R, Klepstad, P, Erno, P, Junker, A, Bártolo, A, Castelo Branco Sousa, M, Esteves, F, Martins, A, Oliveira, T, Ponce, P, Mourão, L, Febra, C, Carmo, E, Lopes, V, Póvoa, P, Rezende, A, Costa, H, Moreira, P, Pádua, F, Leite, A, Almeida, E, Alves, M, Sousa, A, Telo, L, Dias, C, Paiva, J, Ribeiro, R, Amaro, P, Carneiro, A, Moreno, R, Matos, R, Afonso, S, Bouw, M, França, C, Rubio, O, Mañez, R, Campiñez, B, Alvarez, M, Jorda, R, Naveira Abeigón, E, Monedero, P, Alemparte Pardavila, E, Garcia del Valle, S, Perez Calvo, C, Palomar, M, Guerrero, F, Caballero Zirena, A, Arribas, M, Bustamante Munguira, E, Ruiz, J, Iglesias, L, Zavala, E, Valencia, M, Blesa Malpica, A, Martinez Sagasti, F, Nieto, M, Aguilar, G, Martinon Torres, F, Lorente, C, Insausti, J, Vegas Pinto, R, Santos, I, Escriba, A, Olaechea, P, Muñoz, E, Antón Caraballo, E, Galdos Anuncibay, P, Lopez Camps, V, Esteban Reboll, F, Estella, A, Bocero, L, Ibañez, A, Pueyo, L, María Jesús, L, Silva, J, Garro, P, Ramos gómez, L, Rovira, A, Martin Delgado, M, Monton Dito, J, Garcia, F, Navarro, J, Latour Perez, J, Albaya, A, Bustinza, A, Sole violán, J, Ugarte Peña, P, Yuste, I, De Rojas Román, J, Vallés, J, Esteban, E, Quintana Tort Martorell, E, Moreno, M, López Ciudad, V, Manzano Ramirez, A, Sánchez Olmedo, J, Borges, M, Amador Amerigo, J, Guerrero Gomez, F, Montejo González, J, Sirvent, J, Mesalles Sanjuan, E, Barcenilla Gaite, F, Serrano, N, Cerdá, E, Lesmes Serrano, A, Garcia Fuentes, C, Macias Pingarrón, J, Espinosa, E, Sanchez Garcia, M, Felices, F, de la Torre Prados, M, Maria Jesus, H, Luis, V, Jara, R, Briones Lopez, M, Posada, P, Galvan, B, Mariscal, F, Gil, B, Sierra, R, Rico Feijoo, J, Corcobado Márquez, C, Izura, J, González, J, Soto Ibáñez, J, Petersen, P, Johansson, L, Blomqvist, H, Peterzén, B, Wyon, N, Stiernstrom, H, Lindström, I, Paulsson, A, Agvald Ohman, C, Petersson, J, Friberg, H, Einar, V, Hammarskjöld, F, Schindele, M, Arvidsson, S, Sellgren, J, Hulting, J, Häggqvist, J, Rudenstam, J, Lind, D, Kokinsky, E, Owall, A, Jacobson, S, Nydahl, A, Atalan, K, Ates, C, Kahveci, A, Fistikci, H, Kaya, A, Ozgencil, E, Kizilkaya, M, Bosnak, M, Bodur, H, Akan, M, Guven, M, Turkoglu, M, Topeli, A, Togal, T, Uzel, N, Akinci, I, Cakar, N, Tugrul, S, Demirkiran, O, Adanir, T, Dogruer, K, Turkmen, A, Guven, H, Ulger, F, Kocak, S, İç Hastalıkları, and OMÜ

Subjects
Male, Pediatrics, Cross-sectional study, health care facilities, manpower, and services, Antibiotics, Resistance, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Prevalence, Drug Resistance, law.invention, Medical microbiology, law, Pathologie maladies infectieuses, Antibiotic, Critically ill, Infection, Aged, Anti-Bacterial Agents, Bacteria, Bacterial Infections, Cross-Sectional Studies, Europe, Female, Hospitalization, Humans, Middle Aged, Treatment Outcome, Drug Resistance, Bacterial, Intensive Care Units, Infectious Diseases, Critically ill -- Care, Mortality rate, Bacterial, Intensive care unit, SAPS II, Beta lactam antibiotics, Research Article, Human, medicine.medical_specialty, medicine.drug_class, Intensive Care Unit, Bacterial Infection, Antibiotic resistance, Internal medicine, Settore MED/41 - ANESTESIOLOGIA, Anti-Bacterial Agent, medicine, Cross-Sectional Studie, business.industry, Aminopeptidases -- Analysis, Klinisk medicin, Polypeptides, Bacterial diseases -- Diagnosis, Antibiotics -- Therapeutic use, Clinical Medicine, business
Abstract

Background: Antimicrobial resistance is an increasing concern in ICUs worldwide. Infection with an antibiotic resistant (ABR) strain of an organism is associated with greater mortality than infection with the non-resistant strain, but there are few data assessing whether being admitted to an intensive care unit (ICU) with high levels of antimicrobial resistance is associated with a worse outcome than being admitted to an ICU with low rates of resistance. The aim of this study was, therefore, to compare the characteristics of infections and antibiotic treatments and patient outcomes in patients admitted to ICUs in countries considered as having high levels of antibiotic resistance and those admitted to ICUs in countries considered as having low levels of antibiotic resistance.Methods: Data from the large, international EPIC II one-day point prevalence study on infections in patients hospitalized in ICUs were used. For the current study, we compared the data obtained from patients from two groups of countries: countries with reported MRSA rates of ≥ 25% (highABR: Greece, Israel, Italy, Malta, Portugal, Spain, and Turkey) and countries with MRSA rates of < 5% (lowABR: Denmark, Finland, Netherlands, Norway, and Sweden).Results: On the study day, 1187/2204 (53.9%) patients in the HighABR ICUs were infected and 255/558 (45.7%) in the LowABR ICUs (P < 0.01). Patients in the HighABR ICUs were more severely ill than those in the LowABR ICUs, as reflected by a higher SAPS II score (35.6 vs 32.7, P < 0.05) and had longer median ICU (12 days vs 5 days) and hospital (24 days vs 16 days) lengths of stay. They also had higher crude ICU (20.0% vs 15.4%) and hospital (27.0% vs 21.5%) mortality rates (both P < 0.05). However, after multivariable adjustment and matched pair analysis there were no differences in ICU or hospital mortality rates between High or LowABR ICU patients overall or among those with infections.Conclusions: Being hospitalized in an ICU in a region with high levels of antimicrobial resistance is not associated per se with a worse outcome., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2014

8. Real-world impact of rotavirus vaccination in European healthcare settings: a systematic literature review

Author

Goran Bencina, Claudio Costantino, Chiara Mameli, Ugne Sabale, Janice Murtagh, Rebecca Newman, Aideen Ahern, Rikal Bhaila, Alejandro Orrico Sanchez, Federico Martinon-Torres, Cristina Carias, Bencina G., Costantino C., Mameli C., Sabale U., Murtagh J., Newman R., Ahern A., Bhaila R., Sanchez A.O., Martinon-Torres F., and Carias C.

Subjects
Immunology, diarrhea, Rotavirus Infections, Drug Discovery, Humans, Children, gastroenteritis, rotavirus, systematic literature review, vaccines, Child, Aged, Pharmacology, Settore MED/38 - Pediatria Generale e Specialistica, rotaviru, Immunization Programs, Vaccination, Rotavirus Vaccines, Infant, Hospitalization, Molecular Medicine, gastroenteriti, Delivery of Health Care
Abstract

INTRODUCTION: Rotavirus is one of the most common pathogens causing diarrhea in children

Published
2022

9. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Author

Gabor G. Kovacs, Stephanie A. Booth, Sebastian Brandner, Penny Norsworthy, Anna Ladogana, Akin Nihat, Herbert Budka, Saima Zafar, Helen Speedy, Antonio Salas, Parvin Ahmed, Holger Hummerich, Gerard H. Jansen, Tze How Mok, Michael D. Geschwind, Beata Sikorska, Maurizio Pocchiari, Christiane Stehmann, Sabina Capellari, Jean-Louis Laplanche, Sven J. van der Lee, Emma Jones, Jean-Charles Lambert, Olga Calero, Pierluigi Gambetti, Ewa Golanska, Serena Aneli, Richard Knight, Giuseppe Matullo, Pawel P. Liberski, Athanasios Dimitriadis, Jerome Whitfield, Hata Karamujić-Čomić, Federico Martinón-Torres, Emmanuelle Viré, Jiri G. Safar, Tracy Campbell, Pascual Sánchez-Juan, Katie Glisic, Anna Bartoletti-Stella, Carla A. Ibrahim-Verbaas, Adriano Aguzzi, Anna Poleggi, Aili Golubjatnikov, Karl Frontzek, Jean Phillipe Brandel, Phillipe Amouyel, Parmjit S. Jat, Zane Jaunmuktane, Simon Mead, Steven J. Collins, Inga Zerr, Liam Quinn, Piero Parchi, Janis Blevins, Elodie Bouaziz-Amar, Brian S. Appleby, Shannon Sarros, Jacqueline M. Linehan, Miguel Calero, Michael B. Coulthart, Stéphane Haïk, John Collinge, James Uphill, Cornelia M. van Duijn, Diseases, Network Centre for Biomedical Research in Neurodegenerative, Jones E., Hummerich H., Vire E., Uphill J., Dimitriadis A., Speedy H., Campbell T., Norsworthy P., Quinn L., Whitfield J., Linehan J., Jaunmuktane Z., Brandner S., Jat P., Nihat A., How Mok T., Ahmed P., Collins S., Stehmann C., Sarros S., Kovacs G.G., Geschwind M.D., Golubjatnikov A., Frontzek K., Budka H., Aguzzi A., Karamujic-Comic H., van der Lee S.J., Ibrahim-Verbaas C.A., van Duijn C.M., Sikorska B., Golanska E., Liberski P.P., Calero M., Calero O., Sanchez-Juan P., Salas A., Martinon-Torres F., Bouaziz-Amar E., Haik S., Laplanche J.-L., Brandel J.-P., Amouyel P., Lambert J.-C., Parchi P., Bartoletti-Stella A., Capellari S., Poleggi A., Ladogana A., Pocchiari M., Aneli S., Matullo G., Knight R., Zafar S., Zerr I., Booth S., Coulthart M.B., Jansen G.H., Glisic K., Blevins J., Gambetti P., Safar J., Appleby B., Collinge J., Mead S., Universidad de Cantabria, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology

Subjects
0301 basic medicine, epidemiology [Creutzfeldt-Jakob Syndrome], Tau protein, Single-nucleotide polymorphism, Genome-wide association study, diagnosis [Creutzfeldt-Jakob Syndrome], Disease, genetics [Genetic Loci], methods [Genome-Wide Association Study], Polymorphism, Single Nucleotide, Creutzfeldt-Jakob Syndrome, PRNP, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Humans, Genetic Predisposition to Disease, ddc:610, genetics [Genetic Predisposition to Disease], Genotyping, Exome sequencing, Genetics, biology, Odds ratio, genetics [Creutzfeldt-Jakob Syndrome], 030104 developmental biology, Genetic Loci, epidemiology [Genetic Predisposition to Disease], biology.protein, genetics [Polymorphism, Single Nucleotide], Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
Abstract

Background Human prion diseases are rare and usually rapidly fatal neurodegenerative disorders, the most common being sporadic Creutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene that encodes prion protein are strong risk factors for sCJD but, although the condition has similar heritability to other neurodegenerative disorders, no other genetic risk loci have been confirmed. We aimed to discover new genetic risk factors for sCJD, and their causal mechanisms. Methods We did a genome-wide association study of sCJD in European ancestry populations (patients diagnosed with probable or definite sCJD identified at national CJD referral centres) with a two-stage study design using genotyping arrays and exome sequencing. Conditional, transcriptional, and histological analyses of implicated genes and proteins in brain tissues, and tests of the effects of risk variants on clinical phenotypes, were done using deep longitudinal clinical cohort data. Control data from healthy individuals were obtained from publicly available datasets matched for country. Findings Samples from 5208 cases were obtained between 1990 and 2014. We found 41 genome-wide significant single nucleotide polymorphisms (SNPs) and independently replicated findings at three loci associated with sCJD risk; within PRNP (rs1799990; additive model odds ratio [OR] 1·23 [95% CI 1·17–1·30], p=2·68 × 10 −15; heterozygous model p=1·01 × 10 −135), STX6 (rs3747957; OR 1·16 [1·10–1·22], p=9·74 × 10 −9), and GAL3ST1 (rs2267161; OR 1·18 [1·12–1·25], p=8·60 × 10 −10). Follow-up analyses showed that associations at PRNP and GAL3ST1 are likely to be caused by common variants that alter the protein sequence, whereas risk variants in STX6 are associated with increased expression of the major transcripts in disease-relevant brain regions. Interpretation We present, to our knowledge, the first evidence of statistically robust genetic associations in sporadic human prion disease that implicate intracellular trafficking and sphingolipid metabolism as molecular causal mechanisms. Risk SNPs in STX6 are shared with progressive supranuclear palsy, a neurodegenerative disease associated with misfolding of protein tau, indicating that sCJD might share the same causal mechanisms as prion-like disorders. Funding Medical Research Council and the UK National Institute of Health Research in part through the Biomedical Research Centre at University College London Hospitals National Health Service Foundation Trust.

Published
2020
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