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1. In the era of digitalisation and biosignatures, is C-reactive protein still the one to beat? - Authors' reply.

Author: Kaforou, M. and Kaforou, M.
Subjects: Laboratory Medicine - Radboud University Medical Center.
Published: 2024

2. Host gene expression signatures to identify infection type and organ dysfunction in children evaluated for sepsis: a multicentre cohort study

Author: Schlapbach, LJ, Ganesamoorthy, D, Wilson, C, Raman, S, George, S, Snelling, PJ, Phillips, N, Irwin, A, Sharp, N, Le Marsney, R, Chavan, A, Hempenstall, A, Bialasiewicz, S, Macdonald, A, Grimwood, K, Kling, JC, Mcpherson, SJ, Blumenthal, A, Kaforou, M, Levin, M, Herberg, JA, Gibbons, KS, Coin, LJM, Schlapbach, LJ, Ganesamoorthy, D, Wilson, C, Raman, S, George, S, Snelling, PJ, Phillips, N, Irwin, A, Sharp, N, Le Marsney, R, Chavan, A, Hempenstall, A, Bialasiewicz, S, Macdonald, A, Grimwood, K, Kling, JC, Mcpherson, SJ, Blumenthal, A, Kaforou, M, Levin, M, Herberg, JA, Gibbons, KS, and Coin, LJM
Abstract: BACKGROUND: Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection. METHODS: This cohort study was done in emergency departments and intensive care units of four hospitals in Queensland, Australia, and recruited children aged 1 month to 17 years who, upon admission, underwent a diagnostic test, including blood cultures, for suspected sepsis. Whole-blood RNA sequencing of blood was performed with Illumina NovaSeq (San Diego, CA, USA). Samples with completed phenotyping, monitoring, and RNA extraction by March 31, 2020, were included in the discovery cohort; samples collected or completed thereafter and by Oct 27, 2021, constituted the Rapid Paediatric Infection Diagnosis in Sepsis (RAPIDS) internal validation cohort. An external validation cohort was assembled from RNA sequencing gene expression count data from the observational European Childhood Life-threatening Infectious Disease Study (EUCLIDS), which recruited children with severe infection in nine European countries between 2012 and 2016. Feature selection approaches were applied to derive novel gene signatures for disease class (bacterial vs viral infection) and disease severity (presence vs absence of organ dysfunction 24 h post-sampling). The primary endpoint was the presence of organ dysfunction 24 h after blood sampling in the presence of confirmed bacterial versus viral infection. Gene signature performance is reported as area under the receiver operating characteristic curves (AUCs) and 95% CI. FINDINGS: Between Sept 25, 2017, and Oct 27, 2021, 907 patients were enrolled. Blood samples from 595 patients were included in the discovery cohort, and samples from 312 children were included in the RAPIDS validation cohort. We derived a ten-gene disease
Published: 2024

3. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

Author: Herberg, J, Shah, P, Voice, M, Calvo-Bado, L, Rivero Calle, I, Morris, S, Nijman, R, Broderick, C, De, T, Eleftheriou, I, Galassini, R, Khanijau, A, Kolberg, L, Kolnik, M, Rudzate, A, Sagmeister, M, Schweintzger, N, Secka, F, Thakker, C, Van der Velden, F, Vermont, C, Vincek, K, Agyeman, P, Cunnington, A, De Groot, R, Emonts, M, Fidler, K, Kuijpers, T, Mommert-Tripon, M, Brengel-Pesce, K, Mallet, F, Moll, H, Paulus, S, Pokorn, M, Pollard, A, Schlapbach, L, Shen, C-F, Tsolia, M, Usuf, E, Van Der Flier, M, Von Both, U, Yeung, S, Zavadska, D, Zenz, W, Wright, V, Carrol, E, Kaforou, M, Martinon-Torres, F, Fink, C, Levin, M, and PERFORM consortium
Abstract: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods. Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings. Of 4,611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3,477 (75%) had uncertain aetiology. 1,061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N.meningitidis (OR: 3.37, 95% CI: 1.92 – 5.99), S.pneumoniae (OR: 3.89, 95% CI: 2.07 – 7.59), Group A streptococcus (OR 2.73, 95% CI 1.13 – 6.09) and E.coli (OR 2.7, 95% CI 1.02 – 6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11 – 0.46), Influenza B (OR 0.12, 95% CI 0.02 – 0.37) and RSV (OR 0.16, 95% CI: 0.06 – 0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23 – 0.72) and EBV (OR 0.71, 95% CI 0.56 – 0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation. Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.
Published: 2023

4. Adeno-associated virus 2 infection in children with non-A–E hepatitis

Author: Ho, A. Orton, R. Tayler, R. Asamaphan, P. Herder, V. Davis, C. Tong, L. Smollett, K. Manali, M. Allan, J. Rawlik, K. McDonald, S.E. Vink, E. Pollock, L. Gannon, L. Evans, C. McMenamin, J. Roy, K. Marsh, K. Divala, T. Holden, M.T.G. Lockhart, M. Yirrell, D. Currie, S. O’Leary, M. Henderson, D. Shepherd, S.J. Jackson, C. Gunson, R. MacLean, A. McInnes, N. Bradley-Stewart, A. Battle, R. Hollenbach, J.A. Henderson, P. Odam, M. Chikowore, P. Oosthuyzen, W. Chand, M. Hamilton, M.S. Estrada-Rivadeneyra, D. Levin, M. Avramidis, N. Pairo-Castineira, E. Vitart, V. Wilkie, C. Cunnington, A. Herberg, J. Kaforou, M. Wright, V. Bellos, E. Broderick, C. Channon-Wells, S. Cooray, S. De, T. D’Souza, G. Elorrieta, L.E. Galassini, R. Habgood-Coote, D. Hamilton, S. Jackson, H. Kavanagh, J. Marjaneh, M.M. Menikou, S. Nichols, S. Nijman, R. Patel, H. Pennisi, I. Powell, O. Reid, R. Shah, P. Vito, O. Whittaker, E. Wilson, C. Womersley, R. Abdulla, A. Darnell, S. Mustafa, S. Georgiou, P. Manzano, J.-R. Moser, N. Pennisi, I. Carter, M. Tibby, S. Cohen, J. Davis, F. Kenny, J. Wellman, P. White, M. Fish, M. Jennings, A. Shankar-Hari, M. Fidler, K. Agranoff, D. Richmond, V. Seal, M. Faust, S. Owen, D. Ensom, R. McKay, S. Mondo, D. Shaji, M. Schranz, R. Rughnani, P. Anpananthar, A. Liebeschuetz, S. Riddell, A. Khalid, N. Malcolm, I.L. Simagan, T. Peters, M. Bamford, A. O’Neill, L. Pathan, N. Daubney, E. White, D. Heightman, M. Eisen, S. Segal, T. Wellings, L. Drysdale, S.B. Branch, N. Hamzah, L. Jarman, H. Nyirenda, M. Capozzi, L. Gardiner, E. Moots, R. Nasher, M. Hanson, A. Linforth, M. O’Riordan, S. Ellis, D. Deep, A. Caro, I. Shackley, F. Bellini, A. Gormley, S. Neshat, S. Scholefield, B.J. Robbins, C. Winmill, H. Paulus, S.C. Pollard, A.J. Anthony, M. Hopton, S. Miller, D. Oliver, Z. Beer, S. Ward, B. Shrestha, S. Pollard, A.J. Gurung, M. Amatya, P. Pokhrel, B. Bijukchhe, S.M. Lubinda, T. Kelly, S. O’Reilly, P. Martinón-Torres, F. Salas, A. González, F.Á. Bello, X. Ben García, M. Carnota, S and Ho, A. Orton, R. Tayler, R. Asamaphan, P. Herder, V. Davis, C. Tong, L. Smollett, K. Manali, M. Allan, J. Rawlik, K. McDonald, S.E. Vink, E. Pollock, L. Gannon, L. Evans, C. McMenamin, J. Roy, K. Marsh, K. Divala, T. Holden, M.T.G. Lockhart, M. Yirrell, D. Currie, S. O’Leary, M. Henderson, D. Shepherd, S.J. Jackson, C. Gunson, R. MacLean, A. McInnes, N. Bradley-Stewart, A. Battle, R. Hollenbach, J.A. Henderson, P. Odam, M. Chikowore, P. Oosthuyzen, W. Chand, M. Hamilton, M.S. Estrada-Rivadeneyra, D. Levin, M. Avramidis, N. Pairo-Castineira, E. Vitart, V. Wilkie, C. Cunnington, A. Herberg, J. Kaforou, M. Wright, V. Bellos, E. Broderick, C. Channon-Wells, S. Cooray, S. De, T. D’Souza, G. Elorrieta, L.E. Galassini, R. Habgood-Coote, D. Hamilton, S. Jackson, H. Kavanagh, J. Marjaneh, M.M. Menikou, S. Nichols, S. Nijman, R. Patel, H. Pennisi, I. Powell, O. Reid, R. Shah, P. Vito, O. Whittaker, E. Wilson, C. Womersley, R. Abdulla, A. Darnell, S. Mustafa, S. Georgiou, P. Manzano, J.-R. Moser, N. Pennisi, I. Carter, M. Tibby, S. Cohen, J. Davis, F. Kenny, J. Wellman, P. White, M. Fish, M. Jennings, A. Shankar-Hari, M. Fidler, K. Agranoff, D. Richmond, V. Seal, M. Faust, S. Owen, D. Ensom, R. McKay, S. Mondo, D. Shaji, M. Schranz, R. Rughnani, P. Anpananthar, A. Liebeschuetz, S. Riddell, A. Khalid, N. Malcolm, I.L. Simagan, T. Peters, M. Bamford, A. O’Neill, L. Pathan, N. Daubney, E. White, D. Heightman, M. Eisen, S. Segal, T. Wellings, L. Drysdale, S.B. Branch, N. Hamzah, L. Jarman, H. Nyirenda, M. Capozzi, L. Gardiner, E. Moots, R. Nasher, M. Hanson, A. Linforth, M. O’Riordan, S. Ellis, D. Deep, A. Caro, I. Shackley, F. Bellini, A. Gormley, S. Neshat, S. Scholefield, B.J. Robbins, C. Winmill, H. Paulus, S.C. Pollard, A.J. Anthony, M. Hopton, S. Miller, D. Oliver, Z. Beer, S. Ward, B. Shrestha, S. Pollard, A.J. Gurung, M. Amatya, P. Pokhrel, B. Bijukchhe, S.M. Lubinda, T. Kelly, S. O’Reilly, P. Martinón-Torres, F. Salas, A. González, F.Á. Bello, X. Ben García, M. Carnota, S
Abstract: An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case–control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10−12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a ‘helper virus’ to support AAV2 replication) and disease susceptibility related to HLA class II status. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
Published: 2023

5. Correction to: Febrile illness in high-risk children: a prospective, international observational study (European Journal of Pediatrics, (2022), 182, 2, (543-554), 10.1007/s00431-022-04642-1)

Author: van der Velden, F.J.S. de Vries, G. Martin, A. Lim, E. von Both, U. Kolberg, L. Carrol, E.D. Khanijau, A. Herberg, J.A. De, T. Galassini, R. Kuijpers, T.W. Martinón-Torres, F. Rivero-Calle, I. Vermont, C.L. Hagedoorn, N.N. Pokorn, M. Pollard, A.J. Schlapbach, L.J. Tsolia, M. Elefhteriou, I. Yeung, S. Zavadska, D. Fink, C. Voice, M. Zenz, W. Kohlmaier, B. Agyeman, P.K.A. Usuf, E. Secka, F. de Groot, R. Levin, M. van der Flier, M. Emonts, M. Cunnington, A. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Powell, O. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M.M. Kim, N. Kim, E. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Shen, C.-F. Liu, C.-C. Wang, S.-M. Salas, A. González, F.Á. Farto, C.B. Barral-Arca, R. Castro, M.´B. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Suárez, C.D. Vicente, L.G. Gómez-Carballa, A. Rial, J.G. Iglesias, P.L. Martinón-Torres, N. Sánchez, J.M.M. Pérez, B.M. Pardo-Seco, J. Rodríguez, L.P. Pischedda, S. Vázquez, S.R. Calle, I.R. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Ora, M.S. Salas, A. Fernández, S.S. Trasorras, C.S. Iglesias, M.V. Balode, A. Barzdina, A. Deksne, D. Gardovska, D. Gravele, D. Grope, I. Meiere, A. Nokalna, I. Pavare, J. Pucuka, Z. Selecka, K. Rudzate, A. Svile, D. Urbane, U.N. Bojang, K. Zaman, S.M.A. Anderson, S. Sarr, A.R.I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Vermont, C.L. Borensztajn, D.M. Tan, C. Zachariasse, J. Dik, W. Agyeman, P.K. Berger, C. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C.R. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Schlapbach, L.J. Carrol, E.D. Cocklin, E. Jennings, R. Johnston, J. Leigh, S. Lewis-Burke, N. Newall, K. Romaine, S. Eleftheriou, I. and van der Velden, F.J.S. de Vries, G. Martin, A. Lim, E. von Both, U. Kolberg, L. Carrol, E.D. Khanijau, A. Herberg, J.A. De, T. Galassini, R. Kuijpers, T.W. Martinón-Torres, F. Rivero-Calle, I. Vermont, C.L. Hagedoorn, N.N. Pokorn, M. Pollard, A.J. Schlapbach, L.J. Tsolia, M. Elefhteriou, I. Yeung, S. Zavadska, D. Fink, C. Voice, M. Zenz, W. Kohlmaier, B. Agyeman, P.K.A. Usuf, E. Secka, F. de Groot, R. Levin, M. van der Flier, M. Emonts, M. Cunnington, A. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Powell, O. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M.M. Kim, N. Kim, E. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Shen, C.-F. Liu, C.-C. Wang, S.-M. Salas, A. González, F.Á. Farto, C.B. Barral-Arca, R. Castro, M.´B. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Suárez, C.D. Vicente, L.G. Gómez-Carballa, A. Rial, J.G. Iglesias, P.L. Martinón-Torres, N. Sánchez, J.M.M. Pérez, B.M. Pardo-Seco, J. Rodríguez, L.P. Pischedda, S. Vázquez, S.R. Calle, I.R. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Ora, M.S. Salas, A. Fernández, S.S. Trasorras, C.S. Iglesias, M.V. Balode, A. Barzdina, A. Deksne, D. Gardovska, D. Gravele, D. Grope, I. Meiere, A. Nokalna, I. Pavare, J. Pucuka, Z. Selecka, K. Rudzate, A. Svile, D. Urbane, U.N. Bojang, K. Zaman, S.M.A. Anderson, S. Sarr, A.R.I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Vermont, C.L. Borensztajn, D.M. Tan, C. Zachariasse, J. Dik, W. Agyeman, P.K. Berger, C. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C.R. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Schlapbach, L.J. Carrol, E.D. Cocklin, E. Jennings, R. Johnston, J. Leigh, S. Lewis-Burke, N. Newall, K. Romaine, S. Eleftheriou, I.
Abstract: In the original published version of the above article, the names of members of the PERFORM consortium were not introduced in the authorship section. The names are now properly displayed. The complete consortium list has been added as Supplementary material to the original article. The original article has been corrected. © 2023, The Author(s).
Published: 2023

6. A Novel Combination of Host Protein Biomarkers to Distinguish Bacterial From Viral Infections in Febrile Children in Emergency Care.

Author: Tan, C.D., Broek, B. van den, Womersley, R.S., Kaforou, M., Hagedoorn, N.N., Flier, M. van der, Jackson, H., Moll, H.A., Snijder, R., Jonge, M.I. de, Vermont, C.L., Tan, C.D., Broek, B. van den, Womersley, R.S., Kaforou, M., Hagedoorn, N.N., Flier, M. van der, Jackson, H., Moll, H.A., Snijder, R., Jonge, M.I. de, and Vermont, C.L.
Abstract: Item does not contain fulltext, BACKGROUND: Distinguishing bacterial and viral infections based on clinical symptoms in febrile children attending the emergency department (ED) is challenging. The aim of this study is to determine a novel combination of host protein biomarkers and to assess its performance in distinguishing between bacterial and viral infection in febrile children attending EDs. METHODS: A literature search was performed to identify blood protein biomarkers able to distinguish bacterial and viral infections (May 2015-May 2019). We selected 7 protein biomarkers: Procalcitonin, TNF-related apoptosis-inducing ligand (TRAIL), interleukin (IL)-4, IL-6, Interferon gamma-induced protein-10 (CXCL-10), interferon-gamma and lipocalin 2 (LCN2). These were measured in blood plasma using a bead-based immunoassay in children with a confirmed bacterial or viral infection attending EDs in the Netherlands. We used generalized linear modeling to classify bacterial and viral infections and applied a previously developed feature selection algorithm to select the optimal combination of proteins. We performed a subgroup analysis of this protein signature in patients with C-reactive protein <60 mg/L, representing a clinically challenging diagnostic group. RESULTS: In total 102 children were included (N = 67 bacterial; N = 35 viral). Individual performance of the 7 biomarkers in classifying bacterial versus viral infections ranged from 60.8%-74.5% area under the receiver operator curve (AUC). TRAIL, LCN2 and IL-6 were identified as the best 3-protein signature with an AUC of 86% (95% CI: 71.3%-100%). In 57 patients with C-reactive protein levels <60 mg/L, the 3-protein signature had an AUC of 85.1% (95% CI: 75.3%-94.9%). CONCLUSION: We demonstrate a promising novel combination of 3 host protein biomarkers; TRAIL, LCN2 and IL-6, which performs well in classifying bacterial and viral infections in febrile children in emergency care.
Published: 2023

7. Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

Author: Habgood-Coote, D., Wilson, C., Shimizu, C., Barendregt, A.M., Philipsen, R., Galassini, R., Calle, I.R., Workman, L., Agyeman, P.K.A., Ferwerda, G., Anderson, S.T., Berg, J.M. van den, Emonts, M., Carrol, E.D., Fink, C.G., Groot, R. de, Hibberd, M.L., Kanegaye, J., Nicol, M.P., Paulus, S., Pollard, A.J., Salas, A., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Walther, M., Zenz, W., Flier, M. van der, Zar, H.J., Kuijpers, T., Burns, J.C., Martinón-Torres, F., Wright, V.J., Coin, L.J.M., Cunnington, A.J., Herberg, Jethro A., Levin, M., Kaforou, M., Habgood-Coote, D., Wilson, C., Shimizu, C., Barendregt, A.M., Philipsen, R., Galassini, R., Calle, I.R., Workman, L., Agyeman, P.K.A., Ferwerda, G., Anderson, S.T., Berg, J.M. van den, Emonts, M., Carrol, E.D., Fink, C.G., Groot, R. de, Hibberd, M.L., Kanegaye, J., Nicol, M.P., Paulus, S., Pollard, A.J., Salas, A., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Walther, M., Zenz, W., Flier, M. van der, Zar, H.J., Kuijpers, T., Burns, J.C., Martinón-Torres, F., Wright, V.J., Coin, L.J.M., Cunnington, A.J., Herberg, Jethro A., Levin, M., and Kaforou, M.
Abstract: Contains fulltext : 296516.pdf (Publisher’s version ) (Open Access), BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.
Published: 2023

8. Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens.

Author: Willems, E., Gloerich, J., Suppers, Anouk, Flier, M. van der, Heuvel, L.P. van den, Kar, N.C. van de, Philipsen, R., Dael, M.F.P. van, Kaforou, M., Wright, V.J., Herberg, Jethro, Torres, F.M., Levin, M., Groot, R. de, Gool, A.J. van, Lefeber, D.J., Wessels, H.J.C.T., Jonge, M.I. de, Willems, E., Gloerich, J., Suppers, Anouk, Flier, M. van der, Heuvel, L.P. van den, Kar, N.C. van de, Philipsen, R., Dael, M.F.P. van, Kaforou, M., Wright, V.J., Herberg, Jethro, Torres, F.M., Levin, M., Groot, R. de, Gool, A.J. van, Lefeber, D.J., Wessels, H.J.C.T., and Jonge, M.I. de
Abstract: Contains fulltext : 296018.pdf (Publisher’s version ) (Open Access), Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.
Published: 2023

9. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study.

Author: Shah, P., Voice, M., Calvo-Bado, L., Rivero-Calle, I., Morris, S., Nijman, R., Broderick, C., De, T., Eleftheriou, I., Galassini, R., Khanijau, A., Kolberg, L., Kolnik, M., Rudzate, A., Sagmeister, M.G., Schweintzger, N.A., Secka, F., Thakker, C., Velden, F. van der, Vermont, C., Vincek, K., Agyeman, P.K.A., Cunnington, A.J., Groot, R. de, Emonts, M., Fidler, K., Kuijpers, T.W., Mommert-Tripon, M., Brengel-Pesce, K., Mallet, F., Moll, H., Paulus, S., Pokorn, M., Pollard, A., Schlapbach, L.J., Shen, C.F., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Yeung, S., Zavadska, D., Zenz, W., Wright, V., Carrol, E.D., Kaforou, M., Martinon-Torres, F., Fink, C., Levin, M., Herberg, J., Shah, P., Voice, M., Calvo-Bado, L., Rivero-Calle, I., Morris, S., Nijman, R., Broderick, C., De, T., Eleftheriou, I., Galassini, R., Khanijau, A., Kolberg, L., Kolnik, M., Rudzate, A., Sagmeister, M.G., Schweintzger, N.A., Secka, F., Thakker, C., Velden, F. van der, Vermont, C., Vincek, K., Agyeman, P.K.A., Cunnington, A.J., Groot, R. de, Emonts, M., Fidler, K., Kuijpers, T.W., Mommert-Tripon, M., Brengel-Pesce, K., Mallet, F., Moll, H., Paulus, S., Pokorn, M., Pollard, A., Schlapbach, L.J., Shen, C.F., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Yeung, S., Zavadska, D., Zenz, W., Wright, V., Carrol, E.D., Kaforou, M., Martinon-Torres, F., Fink, C., Levin, M., and Herberg, J.
Abstract: 01 september 2023, Contains fulltext : 295917.pdf (Publisher’s version ) (Open Access), BACKGROUND: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. METHODS: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. FINDINGS: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. INTERPRETATION: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which feb
Published: 2023

10. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature.

Author: Jackson, H.R., Miglietta, L., Habgood-Coote, D., D'Souza, G., Shah, P., Nichols, S., Vito, O., Powell, O., Davidson, M.S., Shimizu, C., Agyeman, P.K.A., Beudeker, C.R., Brengel-Pesce, K., Carrol, E.D., Carter, M.J., De, T., Eleftheriou, I., Emonts, M., Epalza, C., Georgiou, P., Groot, R. de, Fidler, K., Fink, C., Keulen, D. van, Kuijpers, T., Moll, H., Papatheodorou, I., Paulus, S., Pokorn, M., Pollard, A.J., Rivero-Calle, I., Rojo, P., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Vermont, C., Yeung, S., Zavadska, D., Zenz, W., Coin, L.J.M., Cunnington, A., Burns, J.C., Wright, V., Martinon-Torres, F., Herberg, Jethro A., Rodriguez-Manzano, J., Kaforou, M., Levin, M., Jackson, H.R., Miglietta, L., Habgood-Coote, D., D'Souza, G., Shah, P., Nichols, S., Vito, O., Powell, O., Davidson, M.S., Shimizu, C., Agyeman, P.K.A., Beudeker, C.R., Brengel-Pesce, K., Carrol, E.D., Carter, M.J., De, T., Eleftheriou, I., Emonts, M., Epalza, C., Georgiou, P., Groot, R. de, Fidler, K., Fink, C., Keulen, D. van, Kuijpers, T., Moll, H., Papatheodorou, I., Paulus, S., Pokorn, M., Pollard, A.J., Rivero-Calle, I., Rojo, P., Secka, F., Schlapbach, L.J., Tremoulet, A.H., Tsolia, M., Usuf, E., Flier, M. van der, Both, U. von, Vermont, C., Yeung, S., Zavadska, D., Zenz, W., Coin, L.J.M., Cunnington, A., Burns, J.C., Wright, V., Martinon-Torres, F., Herberg, Jethro A., Rodriguez-Manzano, J., Kaforou, M., and Levin, M.
Abstract: Contains fulltext : 294537.pdf (Publisher’s version ) (Open Access), BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
Published: 2023

11. Asymptomatic Plasmodium falciparum infection evades triggering a host transcriptomic response

Author: Ahu Prah, D, Dunican, C, Amoah, L, Moradi Marjaneh, M, Kaforou, M, Nordgren, A, Jones-Warner, W, Aniweh, Y, Awandare, G, Cunnington, A, and Hafalla, J
Published: 2023

12. A Novel Combination of Host Protein Biomarkers to Distinguish Bacterial From Viral Infections in Febrile Children in Emergency Care

Author: Tan CD, van den Broek B, Womersley R, Kaforou M, Hagedoorn N, van der Flier M, Jackson H, Moll HA, Snijder R, de Jonge MI, Vermont CL, On behalf of PERFORM Consortium
Published: 2023
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13. Discrimination of bacterial and viral infection using host-RNA signatures integrated in a lab-on-a-chip technology

Author: Pennisi, I, Moniri, A, Miscourides, N, Miglietta, L, Moser, N, Habgood-Coote, D, Herberg, J, Levin, M, Kaforou, M, Rodriguez-Manzano, J, and Georgiou, P
Abstract: The unmet clinical need for accurate point-of-care (POC) diagnostic tests able to discriminate bacterial from viral infection demands a solution that can be used both within healthcare settings and in the field and that can also stem the tide of antimicrobial resistance. Our approach to solve this problem is to combine the use of Host-gene signatures with our Lab-on-a-chip (LoC) technology enabling low-cost LoC expression analysis to detect Infectious Disease.Host-gene expression signatures have been extensively study as a potential tool to be implemented in the diagnosis of infectious disease. On the other hand LoC technologies using Ion-sensitive field-effect transistor (ISFET) arrays, in conjunction with isothermal chemistries, are offering a promising alternative to conventional lab-based nucleic acid amplification instruments, owing to their portable and affordable nature. Currently, the data analysis of ISFET arrays are restricted to established methods by averaging the output of every sensor to give a single time-series. This simple approach makes unrealistic assumptions, leading to insufficient performance for applications that require accurate quantification such as RNA host transcriptomics. In order to reliably quantify host-gene expression on our LoC platform enabling the classification of bacterial and viral infection on chip, we propose a novel data-driven algorithm for extracting time-to-positive values from ISFET arrays. The algorithm proposed is based on modelling sensor drift with adaptive signal processing and clustering sensors based on their behaviour with unsupervised learning methods. Results show that the approach correctly outputs a time-to-positive for all the reactions, with a high correlation to RT-qLAMP (0.85, R2 = 0.98, p < 0.01), resulting in a classification accuracy of 100 % (CI, 95 - 100). By leveraging more advanced data processing methods for ISFET arrays, this work aims to bridge the gap between translating assays from microarray analysis (expensive lab-based discovery method) to ISFET arrays (cheap point-of-care diagnostics) providing benefits on tackling infectious disease outbreak and diagnostic testing in hard-to-reach areas of the world.
Published: 2022

14. TIPICO X: report of the 10th interactive infectious disease workshop on infectious diseases and vaccines

Author: Rivero-Calle, I, Gómez-Rial, J, Bont, L, Gessner, BD, Kohn, M, Dagan, R, Payne, DC, Bruni, L, Pollard, AJ, García-Sastre, A, Faustman, DL, Osterhaus, A, Butler, R, Giménez Sánchez, F, Álvarez, F, Kaforou, M, Bello, X, and Martinón-Torres, F
Subjects: Pharmacology, Infectious disease, Vaccination, Immunology, emergent virus, off-target effects, Meeting Report, Communicable Diseases, zoonoses, transcriptomics, vaccine-preventable diseases, vaccine resilience, Spain, big data, Respiratory Syncytial Virus, Human, BCG Vaccine, Animals, Humans, RNA gene signatures, vaccine hesitancy, Immunology and Allergy
Abstract: TIPICO is an expert meeting and workshop that aims to provide the most recent evidence in the field of infectious diseases and vaccination. The 10th Interactive Infectious Disease TIPICO workshop took place in Santiago de Compostela, Spain, on November 21–22, 2019. Cutting-edge advances in vaccination against respiratory syncytial virus, Streptococcus pneumoniae, rotavirus, human papillomavirus, Neisseria meningitidis, influenza virus, and Salmonella Typhi were discussed. Furthermore, heterologous vaccine effects were updated, including the use of Bacillus Calmette-Guérin (BCG) vaccine as potential treatment for type 1 diabetes. Finally, the workshop also included presentations and discussion on emergent virus and zoonoses, vaccine resilience, building and sustaining confidence in vaccination, approaches to vaccine decision-making, pros and cons of compulsory vaccination, the latest advances in decoding infectious diseases by RNA gene signatures, and the application of big data approaches.
Published: 2020
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15. Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study

Author: Tan, C.D. van der Walle, E.E.P.L. Vermont, C.L. von Both, U. Carrol, E.D. Eleftheriou, I. Emonts, M. van der Flier, M. de Groot, R. 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. Moll, H.A. Levin, M. Cunnington, A. De, T. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Galassini, R. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M. Kim, E. Pierce, B. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Liu, C.-C. Wang, S.-M. Martinón-Torres, F. Salas, A. Álvez González, F. Balo Farto, C. Barral-Arca, R. Barreiro Castro, M. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Durán Suárez, C. García Vicente, L. Gómez-Carballa, A. Gómez Rial, J. Leboráns Iglesias, P. Martinón-Torres, F. Martinón-Torres, N. Martinón Sánchez, J.M. Mosquera Pérez, B. Pardo-Seco, J. Piñeiro Rodríguez, L. Pischedda, S. Vázquez, S.R. Rivero Calle, I. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Sadiki Ora, M. Salas, A. Serén Fernández, S. Serén Trasorras, C. Vilas Iglesias, M. Zavadska, D. Balode, A. Bārzdiņa, A. Deksne, D. Gardovska, D. Grāvele, D. Grope, I. Meiere, A. Nokalna, I. Pavāre, J. Pučuka, Z. Selecka, K. Sidorova, A. Svile, D. Urbāne, U.N. Usuf, E. Bojang, K. Zaman, S.M.A. Secka, F. Anderson, S. Roca, A. Sarr, I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Borensztajn, D.M. Hagedoorn, N.N. Tan, C. Vermont, C.L. Zachariasse, J. Dik, W. Agyeman, P. Schlapbach, L.J. Aebi, C. Wyss, V. Usman, M. Agyeman, P. Schlapbach, L.J. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Berger, C. Carrol, E.D. Paulus and Tan, C.D. van der Walle, E.E.P.L. Vermont, C.L. von Both, U. Carrol, E.D. Eleftheriou, I. Emonts, M. van der Flier, M. de Groot, R. 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. Moll, H.A. Levin, M. Cunnington, A. De, T. Herberg, J. Kaforou, M. Wright, V. Baumard, L. Bellos, E. D’Souza, G. Galassini, R. Habgood-Coote, D. Hamilton, S. Hoggart, C. Hourmat, S. Jackson, H. Maconochie, I. Menikou, S. Lin, N. Nichols, S. Nijman, R. Pena Paz, I. Shah, P. Shen, C.-F. Vito, O. Wilson, C. Abdulla, A. Ali, L. Darnell, S. Jorgensen, R. Mustafa, S. Persand, S. Stevens, M. Kim, E. Pierce, B. Fidler, K. Dudley, J. Richmond, V. Tavliavini, E. Liu, C.-C. Wang, S.-M. Martinón-Torres, F. Salas, A. Álvez González, F. Balo Farto, C. Barral-Arca, R. Barreiro Castro, M. Bello, X. García, M.B. Carnota, S. Cebey-López, M. Curras-Tuala, M.J. Durán Suárez, C. García Vicente, L. Gómez-Carballa, A. Gómez Rial, J. Leboráns Iglesias, P. Martinón-Torres, F. Martinón-Torres, N. Martinón Sánchez, J.M. Mosquera Pérez, B. Pardo-Seco, J. Piñeiro Rodríguez, L. Pischedda, S. Vázquez, S.R. Rivero Calle, I. Rodríguez-Tenreiro, C. Redondo-Collazo, L. Sadiki Ora, M. Salas, A. Serén Fernández, S. Serén Trasorras, C. Vilas Iglesias, M. Zavadska, D. Balode, A. Bārzdiņa, A. Deksne, D. Gardovska, D. Grāvele, D. Grope, I. Meiere, A. Nokalna, I. Pavāre, J. Pučuka, Z. Selecka, K. Sidorova, A. Svile, D. Urbāne, U.N. Usuf, E. Bojang, K. Zaman, S.M.A. Secka, F. Anderson, S. Roca, A. Sarr, I. Saidykhan, M. Darboe, S. Ceesay, S. D’alessandro, U. Moll, H.A. Borensztajn, D.M. Hagedoorn, N.N. Tan, C. Vermont, C.L. Zachariasse, J. Dik, W. Agyeman, P. Schlapbach, L.J. Aebi, C. Wyss, V. Usman, M. Agyeman, P. Schlapbach, L.J. Giannoni, E. Stocker, M. Posfay-Barbe, K.M. Heininger, U. Bernhard-Stirnemann, S. Niederer-Loher, A. Kahlert, C. Natalucci, G. Relly, C. Riedel, T. Aebi, C. Berger, C. Carrol, E.D. Paulus
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
Published: 2022

16. Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria.

Author: Georgiadou, A, Dunican, C, Soro-Barrio, P, Lee, HJ, Kaforou, M, Cunnington, AJ, Georgiadou, A, Dunican, C, Soro-Barrio, P, Lee, HJ, Kaforou, M, and Cunnington, AJ
Abstract: Recent initiatives to improve translation of findings from animal models to human disease have focussed on reproducibility but quantifying the relevance of animal models remains a challenge. Here, we use comparative transcriptomics of blood to evaluate the systemic host response and its concordance between humans with different clinical manifestations of malaria and five commonly used mouse models. Plasmodium yoelii 17XL infection of mice most closely reproduces the profile of gene expression changes seen in the major human severe malaria syndromes, accompanied by high parasite biomass, severe anemia, hyperlactatemia, and cerebral microvascular pathology. However, there is also considerable discordance of changes in gene expression between the different host species and across all models, indicating that the relevance of biological mechanisms of interest in each model should be assessed before conducting experiments. These data will aid the selection of appropriate models for translational malaria research, and the approach is generalizable to other disease models.
Published: 2022

17. 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

18. Supplement to: Diagnosis of childhood tuberculosis and host RNA expres- sion in Africa.

Author: Anderson, S T, Kaforou, M, and Brent, A J
Published: 2014

19. Discovery and validation of a 3-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations; a case-control then observational cohort study

Author: Li, HK, Kaforou, M, Rodriguez-Manzano, J, Channon-Wells, S, Monir, A, Habgood-Coote, D, Gupta, RK, Mills, EA, Lin, J, Chiu, Y-H, Pennisi, I, Miglietta, L, Mehta, R, Obaray, N, Herberg, JA, Wright, VJ, Georgiou, P, Shallcross, LJ, Mentzer, AJ, Levin, M, Cooke, GS, Noursadeghi, M, Sriskandan, S, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), National Institute for Health Research, UK Research and Innovation, and European Commission
Abstract: Background: Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We sought to derive and validate a blood transcriptional signature to detect viral infections including COVID-19 among adults with suspected infection presenting to the Emergency Department (ED). Methods: Blood RNA sequencing was performed on a discovery cohort of adults attending the ED with suspected infection who had subsequently-confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes were subjected to feature selection to derive the most parsimonious discriminating signature. RT-qPCR validation of the signature was then performed in a prospective cohort of ED patients presenting with undifferentiated fever, and a second case-control cohort of ED patients with COVID-19 or bacterial infection. Signature performance was assessed by calculating area under receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities. Findings: A 3-gene transcript signature was derived from the discovery cohort of 56 bacterial and 27 viral infection cases. In the validation cohort of 200 cases, the signature differentiated bacterial from viral infections with an AUC-ROC of 0.976 (95% CI: 0.919-1.000), sensitivity 97.3% and specificity of 100%. The AUC-ROC for C-reactive protein (CRP) and leucocyte count (WCC) was 0.833 (95% CI: 0.694-0.944) and 0.938 (95% CI: 0.840-0.986) respectively. The signature achieved higher net benefit in decision curve analysis than either CRP or WCC for discriminating viral infections from all other cases. In the second validation analysis the signature discriminated 35 bacterial infections from 34 SARS-CoV-2 positive COVID-19 infections with AUC-ROC of 0.953 (95% CI: 0.893-0.992), sensitivity 88.6% and specificity of 94.1%. Interpretation: This novel 3-gene signature discriminates viral infections including COVID-19 from other emergency infection presentations in adults, outperforming both WCC and CRP, thus potentially providing significant clinical utility in managing acute presentations with infection.
Published: 2021

20. Diagnostic criteria for acute FPIES: What are we missing?

Author: Gomez-Carballa, A., Boyle, R., Herberg, J., Kaforou, M., Riggioni, C., Plaza-Martin, A.M., Pascal, M., Garriga-Baraut, T., Garcia-Moral, A., Moreno, M.V., Mayorga, L., Fernandez-Rivas, M.M., Bracamonte, T., Quevedo, S., O’Valle, V., Hernandez, N., Moure, J.D., Garcia-Magan, C., Salas-Ellacuariaga, A., Gomez-Rial, J., Carballeira, I., Figueroa, A., Mangone, G., Mori, F., Liccioli, G., Arasi, S., Fiocchi, A., Pecora, V., Di Stasio, F., Vazquez-Ortiz, Marta, Argiz, Laura, Machinena, Adrianna, Echeverria, Luis, Blasco, Cristina, Prieto, Ana, Infante, Sonsoles, Vila, Leticia, Garcia, Emilio, Gonzalez-Delgado, Purificación, Vazquez-Cortes, Sonia, Barni, Simona, and Martinon-Torres, Frederico
Published: 2020
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21. 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. Domínguez, 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-Napierała, 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. Taylor, A. 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. BATS Consortium
Subjects: hemic and lymphatic diseases
Abstract: BACKGROUND Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS We 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. RESULTS Data 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. CONCLUSIONS We 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. Copyright © 2021 Massachusetts Medical Society.
Published: 2021

22. 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. Domínguez, 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. Man and 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. Domínguez, 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. Man
Abstract: BACKGROUND Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2. METHODS We 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. RESULTS Data 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. CONCLUSIONS We
Published: 2021

23. Kawasaki Disease Patient Stratification and Pathway Analysis Based on Host Transcriptomic and Proteomic Profiles

Author: Jackson, H., Menikou, S., Hamilton, S., McArdle, A., Shimizu, C., Galassini, R., Huang, H., Kim, J., Tremoulet, A., Thorne, A., Fischer, R., Jonge, M.I. de, Kuijpers, T., Wright, V., Burns, J.C., Casals-Pascual, C., Herberg, J., Levin, M., Kaforou, M., Perform, C. On Behalf Of Th, Jackson, H., Menikou, S., Hamilton, S., McArdle, A., Shimizu, C., Galassini, R., Huang, H., Kim, J., Tremoulet, A., Thorne, A., Fischer, R., Jonge, M.I. de, Kuijpers, T., Wright, V., Burns, J.C., Casals-Pascual, C., Herberg, J., Levin, M., Kaforou, M., and Perform, C. On Behalf Of Th
Abstract: Contains fulltext : 234041.pdf (Publisher’s version ) (Open Access), The aetiology of Kawasaki disease (KD), an acute inflammatory disorder of childhood, remains unknown despite various triggers of KD having been proposed. Host 'omic profiles offer insights into the host response to infection and inflammation, with the interrogation of multiple 'omic levels in parallel providing a more comprehensive picture. We used differential abundance analysis, pathway analysis, clustering, and classification techniques to explore whether the host response in KD is more similar to the response to bacterial or viral infections at the transcriptomic and proteomic levels through comparison of 'omic profiles from children with KD to those with bacterial and viral infections. Pathways activated in patients with KD included those involved in anti-viral and anti-bacterial responses. Unsupervised clustering showed that the majority of KD patients clustered with bacterial patients on both 'omic levels, whilst application of diagnostic signatures specific for bacterial and viral infections revealed that many transcriptomic KD samples had low probabilities of having bacterial or viral infections, suggesting that KD may be triggered by a different process not typical of either common bacterial or viral infections. Clustering based on the transcriptomic and proteomic responses during KD revealed three clusters of KD patients on both 'omic levels, suggesting heterogeneity within the inflammatory response during KD. The observed heterogeneity may reflect differences in the host response to a common trigger, or variation dependent on different triggers of the condition.
Published: 2021

24. Identification of Reduced Host Transcriptomic Signatures for Tuberculosis Disease and Digital PCR-Based Validation and Quantification

Author: Gliddon, HD, Kaforou, M, Alikian, M, Habgood-Coote, D, Zhou, C, Oni, T, Anderson, ST, Brent, AJ, Crampin, AC, Eley, B, Heyderman, R, Kern, F, Langford, PR, Ottenhoff, THM, Hibberd, ML, French, N, Wright, VJ, Dockrell, HM, Coin, LJ, Wilkinson, RJ, Levin, M, Gliddon, HD, Kaforou, M, Alikian, M, Habgood-Coote, D, Zhou, C, Oni, T, Anderson, ST, Brent, AJ, Crampin, AC, Eley, B, Heyderman, R, Kern, F, Langford, PR, Ottenhoff, THM, Hibberd, ML, French, N, Wright, VJ, Dockrell, HM, Coin, LJ, Wilkinson, RJ, and Levin, M
Abstract: Recently, host whole blood gene expression signatures have been identified for diagnosis of tuberculosis (TB). Absolute quantification of the concentrations of signature transcripts in blood have not been reported, but would facilitate diagnostic test development. To identify minimal transcript signatures, we applied a transcript selection procedure to microarray data from African adults comprising 536 patients with TB, other diseases (OD) and latent TB (LTBI), divided into training and test sets. Signatures were further investigated using reverse transcriptase (RT)-digital PCR (dPCR). A four-transcript signature (GBP6, TMCC1, PRDM1, and ARG1) measured using RT-dPCR distinguished TB patients from those with OD (area under the curve (AUC) 93.8% (CI95% 82.2-100%). A three-transcript signature (FCGR1A, ZNF296, and C1QB) differentiated TB from LTBI (AUC 97.3%, CI95%: 93.3-100%), regardless of HIV. These signatures have been validated across platforms and across samples offering strong, quantitative support for their use as diagnostic biomarkers for TB.
Published: 2021

25. Interferon-Induced Protein 44 and Interferon-Induced Protein 44-Like Restrict Replication of Respiratory Syncytial Virus

Author: Busse, D. C., primary, Habgood-Coote, D., additional, Clare, S., additional, Brandt, C., additional, Bassano, I., additional, Kaforou, M., additional, Herberg, J., additional, Levin, M., additional, Eléouët, J.-F., additional, Kellam, P., additional, and Tregoning, J. S., additional
Published: 2020
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26. Diagnostic criteria for acute FPIES: What are we missing?

Author: Vazquez-Ortiz, Marta, primary, Argiz, Laura, additional, Machinena, Adrianna, additional, Echeverria, Luis, additional, Blasco, Cristina, additional, Prieto, Ana, additional, Infante, Sonsoles, additional, Vila, Leticia, additional, Garcia, Emilio, additional, Gonzalez-Delgado, Purificación, additional, Vazquez-Cortes, Sonia, additional, Barni, Simona, additional, Martinon-Torres, Frederico, additional, Gomez-Carballa, A., additional, Boyle, R., additional, Herberg, J., additional, Kaforou, M., additional, Riggioni, C., additional, Plaza-Martin, A.M., additional, Pascal, M., additional, Garriga-Baraut, T., additional, Garcia-Moral, A., additional, Moreno, M.V., additional, Mayorga, L., additional, Fernandez-Rivas, M.M., additional, Bracamonte, T., additional, Quevedo, S., additional, O’Valle, V., additional, Hernandez, N., additional, Moure, J.D., additional, Garcia-Magan, C., additional, Salas-Ellacuariaga, A., additional, Gomez-Rial, J., additional, Carballeira, I., additional, Figueroa, A., additional, Mangone, G., additional, Mori, F., additional, Liccioli, G., additional, Arasi, S., additional, Fiocchi, A., additional, Pecora, V., additional, and Di Stasio, F., additional
Published: 2020
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27. Viral and bacterial infection elicit distinct changes in plasma lipids in febrile children

Author: Wang, X, Nijman, R, Camuzeaux, S, Sands, C, Jackson, H, Kaforou, M, Emonts, M, Herberg, J, Maconochie, I, Carrol, E, Paulus, S, Zenz, W, Van der Flier, M, De Groot, R, Martinon-Torres, F, Schlapbach, L, Pollard, A, Fink, C, Kuijpers, T, Anderson, S, Lewis, M, Levin, M, McClure, M, and On behalf of EUCLIDS consortium
Subjects: on behalf of EUCLIDS consortium
Abstract: Fever is the most common reason that children present to Emergency Departments in the UK. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. As a result, many children are prescribed antibiotics often unnecessarily, while others with life-threatening bacterial infections can remain untreated. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection elicit distinct changes in the host lipidome. Glycerophosphoinositol, sphingomyelin, lysophosphotidylcholine and cholesterol sulfate were increased in the confirmed virus infected group, while fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were increased in cases with confirmed bacterial infection. A combination of three lipids achieved the area under the receiver operating characteristic (ROC) curve of 0.918 (95% CI 0.835 to 1). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.
Published: 2019

28. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Author: Secka, F, Herberg, J A, Sarr, I, Darboe, S, Sey, G, Saidykhan, M, Wathuo, M, Kaforou, M, Antonio, M, Roca, A, Zaman, S M A, Cebey-López, M, Boeddha, N P, Paulus, S, Kohlfürst, D S, Emonts, M, Zenz, W, Carrol, E D, de Groot, R, Schlapbach, L, Martinon-Torres, F, Bojang, K, Levin, M, van der Flier, M, Anderson, S T, Pediatrics, European Commission, Imperial College London, Wellcome Trust, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: Oncology, children, antibiotic, Major Article, Clinical Neurology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Gambia, bacteremia, mortality
Abstract: Contains fulltext : 215757.pdf (Publisher’s version ) (Open Access) Background: The limited availability of microbiology services in sub-Saharan Africa impedes accurate diagnosis of bacterial pathogens and understanding of trends in prevalence and antibiotic sensitivities. We aimed to characterize bacteremia among hospitalized children in The Gambia and to identify factors associated with bacteremia and mortality. Methods: We prospectively studied children presenting with suspected severe infection to 2 urban hospitals in The Gambia, between January 2013 and September 2015. Demographic and anthropometric data, clinical features, management, and blood culture results were documented. Urine screens for antibiotic activity were performed in a subset of participants. Results: Of 411 children enrolled (median age, 29 months; interquartile range, 11-82), 79.5% (325 of 409) reported prehospital antibiotic use. Antimicrobial activity by urinary screen for antibiotic activity was detected in 70.8% (n = 80 of 113). Sixty-six bacterial pathogens were identified in 65 (15.8%) participants and Staphylococcus aureus predominated. Gram-positive organisms were more commonly identified than Gram-negative (P < .01). Antibiotic resistance against first-line antimicrobials (ampicillin and gentamicin) was common among Gram-negative bacteria (39%; range, 25%-100%). Factors significantly associated with bacteremia included the following: gender, hydration status, musculoskeletal examination findings, admission to the Medical Research Council The Gambia at London School of Hygiene & Tropical Medicine hospital, and meeting sepsis criteria. Those associated with increased mortality were presence of a comorbidity, clinical pallor, tachypnea, and altered consciousness. Tachycardia was associated with reduced mortality. Conclusions: The bacteremia rate in children with suspected childhood life-threatening infectious diseases in The Gambia is high. The pattern of pathogen prevalence and antimicrobial resistance has changed over time compared with previous studies illustrating the importance of robust bacterial surveillance programs in resource-limited settings.
Published: 2019

29. Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy

Author: Montaldo, P, Kaforou, M, Pollara, G, Hervas-Marin, D, Calabria, I, Panadero, J, Pedrola, L, Lally, PJ, Oliveira, V, Kage, A, Atreja, G, Mendoza, J, Soe, A, Pattnayak, S, Shankaran, S, Vento, M, Herberg, J, Thayyil, S, Medical Research Council, and National Institute for Health Research
Subjects: MOUSE-BRAIN, Science & Technology, BIRTH, 1103 Clinical Sciences, PROFILES, Neonatal encephalopathy, Pediatrics, REOXYGENATION, INFECTION, 1114 Paediatrics and Reproductive Medicine, Gene expression, NONCODING RNA MALAT1, Brain injury, Life Sciences & Biomedicine, Biomarkers
Abstract: Background: Variable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies; hence better disease stratification may facilitate the development of individualized neuroprotective therapies. Objectives: We examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and Methods: We performed next-generation sequencing on whole blood RNA from 12 babies with neonatal encephalopathy and 6 time-matched healthy term babies. Genes significantly differentially expressed between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. Results: We identified 950 statistically significant genes discriminating perfectly between healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p = 0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 signaling and production in macrophages (p = 0.003), and hypoxia-inducible factor 1 alpha signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. Conclusion: Babies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profiles may be useful for disease stratification and for developing personalized neuroprotective therapies. (C) The Author(s). Published by S. Karger AG, Basel
Published: 2018

30. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, X, Nijman, R., Camuzeaux, S., Sands, C., Jackson, H., Kaforou, M., Emonts, M., Herberg, J.A., Maconochie, I., Carrol, E.D., Paulus, S.C., Zenz, W., Flier, M. van der, Groot, R. de, Martinon-Torres, F., Schlapbach, L.J., Pollard, A.J., Fink, C., Kuijpers, T.T., Anderson, S., Lewis, M.R., Levin, M., McClure, M., Gerrits, G.P.J.M., Neeleman, C., Ziuraite, I, Zukovskaja, V., Wang, X, Nijman, R., Camuzeaux, S., Sands, C., Jackson, H., Kaforou, M., Emonts, M., Herberg, J.A., Maconochie, I., Carrol, E.D., Paulus, S.C., Zenz, W., Flier, M. van der, Groot, R. de, Martinon-Torres, F., Schlapbach, L.J., Pollard, A.J., Fink, C., Kuijpers, T.T., Anderson, S., Lewis, M.R., Levin, M., McClure, M., Gerrits, G.P.J.M., Neeleman, C., Ziuraite, I, and Zukovskaja, V.
Abstract: Contains fulltext : 215499.pdf (publisher's version ) (Open Access), Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.
Published: 2019

31. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Author: Secka, F., Herberg, J.A., Sarr, I., Darboe, S., Sey, G., Saidykhan, M., Wathuo, M., Kaforou, M., Antonio, M., Roca, A., Zaman, S.M.A., Cebey-Lopez, M., Boeddha, N.P., Paulus, S., Kohlfurst, D.S., Emonts, M., Zenz, W., Carrol, E.D., Groot, R. de, Schlapbach, L., Martinon-Torres, F., Bojang, K., Levin, M., Flier, M. van der, Anderson, S.T., Secka, F., Herberg, J.A., Sarr, I., Darboe, S., Sey, G., Saidykhan, M., Wathuo, M., Kaforou, M., Antonio, M., Roca, A., Zaman, S.M.A., Cebey-Lopez, M., Boeddha, N.P., Paulus, S., Kohlfurst, D.S., Emonts, M., Zenz, W., Carrol, E.D., Groot, R. de, Schlapbach, L., Martinon-Torres, F., Bojang, K., Levin, M., Flier, M. van der, and Anderson, S.T.
Abstract: Contains fulltext : 215757.pdf (publisher's version ) (Open Access), Background: The limited availability of microbiology services in sub-Saharan Africa impedes accurate diagnosis of bacterial pathogens and understanding of trends in prevalence and antibiotic sensitivities. We aimed to characterize bacteremia among hospitalized children in The Gambia and to identify factors associated with bacteremia and mortality. Methods: We prospectively studied children presenting with suspected severe infection to 2 urban hospitals in The Gambia, between January 2013 and September 2015. Demographic and anthropometric data, clinical features, management, and blood culture results were documented. Urine screens for antibiotic activity were performed in a subset of participants. Results: Of 411 children enrolled (median age, 29 months; interquartile range, 11-82), 79.5% (325 of 409) reported prehospital antibiotic use. Antimicrobial activity by urinary screen for antibiotic activity was detected in 70.8% (n = 80 of 113). Sixty-six bacterial pathogens were identified in 65 (15.8%) participants and Staphylococcus aureus predominated. Gram-positive organisms were more commonly identified than Gram-negative (P < .01). Antibiotic resistance against first-line antimicrobials (ampicillin and gentamicin) was common among Gram-negative bacteria (39%; range, 25%-100%). Factors significantly associated with bacteremia included the following: gender, hydration status, musculoskeletal examination findings, admission to the Medical Research Council The Gambia at London School of Hygiene & Tropical Medicine hospital, and meeting sepsis criteria. Those associated with increased mortality were presence of a comorbidity, clinical pallor, tachypnea, and altered consciousness. Tachycardia was associated with reduced mortality. Conclusions: The bacteremia rate in children with suspected childhood life-threatening infectious diseases in The Gambia is high. The pattern of pathogen prevalence and antimicrobial resistance has changed over time compared with previous studie
Published: 2019

32. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, X. (Xinzhu), Nijman, R.G. (Ruud), Camuzeaux, S. (Stephane), Sands, C. (Caroline), Jackson, H. (Heather), Kaforou, M. (Myrsini), Emonts, M. (Marieke), Herberg, J.A. (Jethro A.), MacOnochie, I.K. (Ian), Carrol, E.D. (Enitan), Paulus, S.C. (Stephane C.), Zenz, W. (Werner), Flier, M. (Michiel) van der, Groot, R. (Ronald) de, Martinon-Torres, F. (Federico), Schlapbach, L.J. (Luregn), Pollard, A.J. (Andrew J.), Fink, C. (Colin), Kuijpers, T.T. (Taco T.), Anderson, S. (Suzanne), Lewis, M.R. (Matthew R.), Levin, M. (Michael), McClure, M. (Myra), Gormley, S. (Stuart), Hamilton, S. (Shea), Hourmat, B. (Bernardo), Hoggart, C. (Clive), Sancho-Shimizu, V. (Vanessa), Wright, V.J. (Victoria), Abdulla, A. (Amina), Agapow, P. (Paul), Bartlett, M. (Maeve), Bellos, E. (Evangelos), Eleftherohorinou, H. (Hariklia), Galassini, R. (Rachel), Inwald, D. (David), Mashbat, M. (Meg), Menikou, S. (Stefanie), Mustafa, S. (Sobia), Nadel, S. (Simon), Rahman, R. (Rahmeen), Thakker, C. (Clare), Coin, L.M.J. (Lachlan M. J.), Bokhandi, S. (S.), Power, S. (Sue), Barham, H. (Heather), Pathan, D.N. (Dr N), Ridout, J. (Jenna), White, D. (Deborah), Thurston, S. (Sarah), Faust, D. (Dominik), Patel, S.Y. (Smita Y.), McCorkell, J. (Jenni), Davies, P. (P.), Crate, L. (Lindsey), Navarra, H. (Helen), Carter, S. (Stephanie), Ramaiah, R. (R.), Patel, R. (Rekha), Tuffrey, C. (Catherine), Gribbin, A. (Andrew), McCready, S. (Sharon), Peters, M. (Mark), Hardy, K. (Katie), Standing, F. (Fran), O’Neill, L. (Lauren), Abelake, E. (Eugenia), Deep, A. (Akash), Nsirim, E. (Eniola), Willis, L. (Louise), Young, Z. (Zoe), Royad, C. (C.), White, S. (Sonia), Fortune, P.M. (P. M.), Hudnott, P. (Phil), González, F.Á. (Fernando Álvez), Barral-Arca, R. (Ruth), Cebey-López, M. (Miriam), Curras-Tuala, M.J. (María José), García, N. (Natalia), Vicente, L.G. (Luisa García), Gómez-Carballa, A. (Alberto), Rial, J.G. (Jose Gómez), Beiroa, A.G. (Andrea Grela), Grande, A.J. (Antonio Justicia), Iglesias, P.L. (Pilar Leboráns), Santos, A.E.M. (Alba Elena Martínez), Martinón-Torres, F. (Federico), MartinónTorres, N. (Nazareth), Sánchez, J.M.M. (José María Martinón), Gutiérrez, B.M. (Beatriz Morillo), Pérez, B.M. (Belén Mosquera), Pacheco, P.O. (Pablo Obando), Pardo-Seco, J. (Jacobo), Pischedda, S. (Sara), RiveroCalle, I. (Irene), Rodríguez-Tenreiro, C. (Carmen), Redondo-Collazo, L. (Lorenzo), Ellacuriagal, A.S. (Antonio Salas), Fernández, S.S. (Sonia Serén), Silva, M.S.P. (María del Sol Porto), Vega, A. (Ana), Trillo, L.V. (Lucía Vilanova), Salas, A. (Antonio), Reyes, S.B. (Susana Beatriz), León, M.C.L. (María Cruz León), Mingorance, Á.N. (Álvaro Navarro), Barrios, X.G. (Xavier Gabaldó), Vergara, E.O. (Eider Oñate), Torre, A.C. (Andrés Concha), Vivanco, A. (Ana), Fernández, R. (Reyes), Sánchez, F.G. (Francisco Giménez), Forte, M.S. (Miguel Sánchez), Rojo, P. (Pablo), Contreras, J.R. (J. Ruiz), Palacios, A. (Alba), Ibarrondo, C.E. (Cristina Epalza), Cooke, E.F. (Elizabeth Fernández), Navarro, M. (Marisa), Álvarez, C.Á. (Cristina Álvarez), Lozano, M.J. (María José), Carreras, E. (Eduardo), Sanagustín, S.B. (Sonia Brió), Neth, O. (Olaf), Padilla, M.C.M. (Ma del Carmen Martínez), Tato, L.M.P. (Luis Manuel Prieto), Guillén, S. (Sara), Silveira, L.F. (Laura Fernández), Moreno, D. (David), van Furth, A.M.T. (A. M. Tutu), Boeddha, N.P. (Navin), Driessen, G.J.A. (Gertjan), Hazelzet, J.A. (Jan), Pajkrt, D. (D.), Sanders, E.A.M. (E. A.M.), van de Beek, D. (D.), Ende, A. (A.) van der, Philipsen, H.L.A. (H. L.A.), Adeel, A.O.A. (A. O.A.), Breukels, M.A. (M. A.), Brinkman, D.M.C., de Korte, C.C.M.M. (C. C.M.M.), de Vries, E. (E.), Waal, W.J. (Wouter) de, Dekkers, R. (R.), Dings-Lammertink, A. (A.), Doedens, R.A. (R. A.), Donker, A.E. (A.), Dousma, M. (M.), Faber, T.E. (T. E.), Gerrit, G.P.J.M. (Gerardus), Gerver, J.A.M. (J. A.M.), Heidema, J. (Jojanneke), Veen, J.H.-V. (J. Homan-van der), Jacobs, M.A.M. (M. A.M.), Jansen, N.J.G. (N. J.G.), Kawczynski, P. (P.), Klucovska, K. (K.), Kneyber, M.C.J. (M. C.J.), Koopman-Keemink, Y. (Yvonne), Langenhorst, V.J. (V. J.), Leusink, J. (J.), Loza, B.F. (Bettina F.), Merth, I.T. (I. T.), Miedema, C.J. (C. J.), Neeleman, C. (C.), Noordzij, J.G. (Jeroen), Obihara, C.C. (Charlie C.), van Overbeek – van Gils, A.L.T. (A. L.T.), Poortman, G.H. (G. H.), Potgieter, S.T. (S. T.), Potjewijd, J. (J.), Rosias, P.P.R. (Philippe), Sprong, T. (Tom), ten Tussher, G.W. (G. W.), Thio, B.J. (B. J.), Tramper-Stranders, G.A. (Gerdien), Deuren, M. (Marcel) van, van der Meer, H. (H.), van Kuppevelt, A.J.M. (A. J.M.), van Wermeskerken, A.M. (A. M.), Verwijs, W.A. (W. A.), Wolfs, T.F.W. (T. F.W.), Agyeman, P. (Philipp), Aebi, C. (Christoph), Berger, C. (Christoph), Giannoni, P., Stocker, M. (Martin), Posfay-Barbe, K.M. (Klara M.), Heininger, U. (Ulrich), Bernhard-Stirnemann, S. (Sara), Niederer-Loher, A. (Anita), Kahlert, C. (Christian), Hasters, P. (Paul), Relly, C. (Christa), Baer, W. (Walter), Frederick, H. (Hannah), Jennings, R. (Rebecca), Johnston, J. (Joanne), Kenwright, R. (Rhian), Pinnock, E. (Elli), Agbeko, R. (Rachel), Secka, F. (Fatou), Bojang, K. (Kalifa), Sarr, I. (Isatou), Kebbeh, N. (Ngange), Sey, G. (Gibbi), Momodou, (), khan, S. (Saidy), Cole, F. (Fatoumata), Thomas, G. (Gilleh), Antonio, M. (Martin), Klobassa, D.S. (Daniela S.), Binder, A. (Alexander), Schweintzger, N.A. (Nina A.), Sagmeister, M. (Manfred), Baumgart, H. (Hinrich), Baumgartner, M. (Markus), Behrends, U. (Uta), Biebl, A. (Ariane), Birnbacher, R. (Robert), Blanke, J.-G. (Jan-Gerd), Boelke, C. (Carsten), Breuling, K. (Kai), Brunner, J. (Jürgen), Buller, M. (Maria), Dahlem, P. (Peter), Dietrich, B. (Beate), Eber, E. (Ernst), Elias, J. (Johannes), Emhofer, J. (Josef), Etschmaier, R. (Rosa), Farr, S. (Sebastian), Girtler, Y. (Ylenia), Grigorow, I. (Irina), Heimann, K. (Konrad), Ihm, U. (Ulrike), Jaros, Z. (Zdenek), Kalhoff, H. (Hermann), Kaulfersch, W. (Wilhelm), Kemen, C. (Christoph), Klocker, N. (Nina), Köster, B. (Bernhard), Kohlmaier, B. (Benno), Komini, E. (Eleni), Kramer, L. (Lydia), Neubert, A. (Antje), Ortner, D. (Daniel), Pescollderungg, L. (Lydia), Pfurtscheller, K. (Klaus), Reiter, K. (Karl), Ristic, G. (Goran), Rödl, S. (Siegfried), Sellner, A. (Andrea), Sonnleitner, A. (Astrid), Sperl, M. (Matthias), Stelzl, W. (Wolfgang), Till, H. (Holger), Trobisch, A. (Andreas), Vierzig, A. (Anne), Vogel, U. (Ulrich), Weingarten, C. (Christina), Welke, S. (Stefanie), Wimmer, A. (Andreas), Wintergerst, U. (Uwe), Wüller, D. (Daniel), Zaunschirm, A. (Andrew), Ziuraite, I. (Ieva), Žukovskaja, V. (Veslava), Wang, X. (Xinzhu), Nijman, R.G. (Ruud), Camuzeaux, S. (Stephane), Sands, C. (Caroline), Jackson, H. (Heather), Kaforou, M. (Myrsini), Emonts, M. (Marieke), Herberg, J.A. (Jethro A.), MacOnochie, I.K. (Ian), Carrol, E.D. (Enitan), Paulus, S.C. (Stephane C.), Zenz, W. (Werner), Flier, M. (Michiel) van der, Groot, R. (Ronald) de, Martinon-Torres, F. (Federico), Schlapbach, L.J. (Luregn), Pollard, A.J. (Andrew J.), Fink, C. (Colin), Kuijpers, T.T. (Taco T.), Anderson, S. (Suzanne), Lewis, M.R. (Matthew R.), Levin, M. (Michael), McClure, M. (Myra), Gormley, S. (Stuart), Hamilton, S. (Shea), Hourmat, B. (Bernardo), Hoggart, C. (Clive), Sancho-Shimizu, V. (Vanessa), Wright, V.J. (Victoria), Abdulla, A. (Amina), Agapow, P. (Paul), Bartlett, M. (Maeve), Bellos, E. (Evangelos), Eleftherohorinou, H. (Hariklia), Galassini, R. (Rachel), Inwald, D. (David), Mashbat, M. (Meg), Menikou, S. (Stefanie), Mustafa, S. (Sobia), Nadel, S. (Simon), Rahman, R. (Rahmeen), Thakker, C. (Clare), Coin, L.M.J. (Lachlan M. J.), Bokhandi, S. (S.), Power, S. (Sue), Barham, H. (Heather), Pathan, D.N. (Dr N), Ridout, J. (Jenna), White, D. (Deborah), Thurston, S. (Sarah), Faust, D. (Dominik), Patel, S.Y. (Smita Y.), McCorkell, J. (Jenni), Davies, P. (P.), Crate, L. (Lindsey), Navarra, H. (Helen), Carter, S. (Stephanie), Ramaiah, R. (R.), Patel, R. (Rekha), Tuffrey, C. (Catherine), Gribbin, A. (Andrew), McCready, S. (Sharon), Peters, M. (Mark), Hardy, K. (Katie), Standing, F. (Fran), O’Neill, L. (Lauren), Abelake, E. (Eugenia), Deep, A. (Akash), Nsirim, E. (Eniola), Willis, L. (Louise), Young, Z. (Zoe), Royad, C. (C.), White, S. (Sonia), Fortune, P.M. (P. M.), Hudnott, P. (Phil), González, F.Á. (Fernando Álvez), Barral-Arca, R. (Ruth), Cebey-López, M. (Miriam), Curras-Tuala, M.J. (María José), García, N. (Natalia), Vicente, L.G. (Luisa García), Gómez-Carballa, A. (Alberto), Rial, J.G. (Jose Gómez), Beiroa, A.G. (Andrea Grela), Grande, A.J. (Antonio Justicia), Iglesias, P.L. (Pilar Leboráns), Santos, A.E.M. (Alba Elena Martínez), Martinón-Torres, F. (Federico), MartinónTorres, N. (Nazareth), Sánchez, J.M.M. (José María Martinón), Gutiérrez, B.M. (Beatriz Morillo), Pérez, B.M. (Belén Mosquera), Pacheco, P.O. (Pablo Obando), Pardo-Seco, J. (Jacobo), Pischedda, S. (Sara), RiveroCalle, I. (Irene), Rodríguez-Tenreiro, C. (Carmen), Redondo-Collazo, L. (Lorenzo), Ellacuriagal, A.S. (Antonio Salas), Fernández, S.S. (Sonia Serén), Silva, M.S.P. (María del Sol Porto), Vega, A. (Ana), Trillo, L.V. (Lucía Vilanova), Salas, A. (Antonio), Reyes, S.B. (Susana Beatriz), León, M.C.L. (María Cruz León), Mingorance, Á.N. (Álvaro Navarro), Barrios, X.G. (Xavier Gabaldó), Vergara, E.O. (Eider Oñate), Torre, A.C. (Andrés Concha), Vivanco, A. (Ana), Fernández, R. (Reyes), Sánchez, F.G. (Francisco Giménez), Forte, M.S. (Miguel Sánchez), Rojo, P. (Pablo), Contreras, J.R. (J. Ruiz), Palacios, A. (Alba), Ibarrondo, C.E. (Cristina Epalza), Cooke, E.F. (Elizabeth Fernández), Navarro, M. (Marisa), Álvarez, C.Á. (Cristina Álvarez), Lozano, M.J. (María José), Carreras, E. (Eduardo), Sanagustín, S.B. (Sonia Brió), Neth, O. (Olaf), Padilla, M.C.M. (Ma del Carmen Martínez), Tato, L.M.P. (Luis Manuel Prieto), Guillén, S. (Sara), Silveira, L.F. (Laura Fernández), Moreno, D. (David), van Furth, A.M.T. (A. M. Tutu), Boeddha, N.P. (Navin), Driessen, G.J.A. (Gertjan), Hazelzet, J.A. (Jan), Pajkrt, D. (D.), Sanders, E.A.M. (E. A.M.), van de Beek, D. (D.), Ende, A. (A.) van der, Philipsen, H.L.A. (H. L.A.), Adeel, A.O.A. (A. O.A.), Breukels, M.A. (M. A.), Brinkman, D.M.C., de Korte, C.C.M.M. (C. C.M.M.), de Vries, E. (E.), Waal, W.J. (Wouter) de, Dekkers, R. (R.), Dings-Lammertink, A. (A.), Doedens, R.A. (R. A.), Donker, A.E. (A.), Dousma, M. (M.), Faber, T.E. (T. E.), Gerrit, G.P.J.M. (Gerardus), Gerver, J.A.M. (J. A.M.), Heidema, J. (Jojanneke), Veen, J.H.-V. (J. Homan-van der), Jacobs, M.A.M. (M. A.M.), Jansen, N.J.G. (N. J.G.), Kawczynski, P. (P.), Klucovska, K. (K.), Kneyber, M.C.J. (M. C.J.), Koopman-Keemink, Y. (Yvonne), Langenhorst, V.J. (V. J.), Leusink, J. (J.), Loza, B.F. (Bettina F.), Merth, I.T. (I. T.), Miedema, C.J. (C. J.), Neeleman, C. (C.), Noordzij, J.G. (Jeroen), Obihara, C.C. (Charlie C.), van Overbeek – van Gils, A.L.T. (A. L.T.), Poortman, G.H. (G. H.), Potgieter, S.T. (S. T.), Potjewijd, J. (J.), Rosias, P.P.R. (Philippe), Sprong, T. (Tom), ten Tussher, G.W. (G. W.), Thio, B.J. (B. J.), Tramper-Stranders, G.A. (Gerdien), Deuren, M. (Marcel) van, van der Meer, H. (H.), van Kuppevelt, A.J.M. (A. J.M.), van Wermeskerken, A.M. (A. M.), Verwijs, W.A. (W. A.), Wolfs, T.F.W. (T. F.W.), Agyeman, P. (Philipp), Aebi, C. (Christoph), Berger, C. (Christoph), Giannoni, P., Stocker, M. (Martin), Posfay-Barbe, K.M. (Klara M.), Heininger, U. (Ulrich), Bernhard-Stirnemann, S. (Sara), Niederer-Loher, A. (Anita), Kahlert, C. (Christian), Hasters, P. (Paul), Relly, C. (Christa), Baer, W. (Walter), Frederick, H. (Hannah), Jennings, R. (Rebecca), Johnston, J. (Joanne), Kenwright, R. (Rhian), Pinnock, E. (Elli), Agbeko, R. (Rachel), Secka, F. (Fatou), Bojang, K. (Kalifa), Sarr, I. (Isatou), Kebbeh, N. (Ngange), Sey, G. (Gibbi), Momodou, (), khan, S. (Saidy), Cole, F. (Fatoumata), Thomas, G. (Gilleh), Antonio, M. (Martin), Klobassa, D.S. (Daniela S.), Binder, A. (Alexander), Schweintzger, N.A. (Nina A.), Sagmeister, M. (Manfred), Baumgart, H. (Hinrich), Baumgartner, M. (Markus), Behrends, U. (Uta), Biebl, A. (Ariane), Birnbacher, R. (Robert), Blanke, J.-G. (Jan-Gerd), Boelke, C. (Carsten), Breuling, K. (Kai), Brunner, J. (Jürgen), Buller, M. (Maria), Dahlem, P. (Peter), Dietrich, B. (Beate), Eber, E. (Ernst), Elias, J. (Johannes), Emhofer, J. (Josef), Etschmaier, R. (Rosa), Farr, S. (Sebastian), Girtler, Y. (Ylenia), Grigorow, I. (Irina), Heimann, K. (Konrad), Ihm, U. (Ulrike), Jaros, Z. (Zdenek), Kalhoff, H. (Hermann), Kaulfersch, W. (Wilhelm), Kemen, C. (Christoph), Klocker, N. (Nina), Köster, B. (Bernhard), Kohlmaier, B. (Benno), Komini, E. (Eleni), Kramer, L. (Lydia), Neubert, A. (Antje), Ortner, D. (Daniel), Pescollderungg, L. (Lydia), Pfurtscheller, K. (Klaus), Reiter, K. (Karl), Ristic, G. (Goran), Rödl, S. (Siegfried), Sellner, A. (Andrea), Sonnleitner, A. (Astrid), Sperl, M. (Matthias), Stelzl, W. (Wolfgang), Till, H. (Holger), Trobisch, A. (Andreas), Vierzig, A. (Anne), Vogel, U. (Ulrich), Weingarten, C. (Christina), Welke, S. (Stefanie), Wimmer, A. (Andreas), Wintergerst, U. (Uwe), Wüller, D. (Daniel), Zaunschirm, A. (Andrew), Ziuraite, I. (Ieva), and Žukovskaja, V. (Veslava)
Abstract: Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are
Published: 2019
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33. Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Author: Borghini, L, Png, E, Binder, A, Wright, VJ, Pinnock, E, de Groot, R, Hazelzet, J, Emonts, M, Van der Flier, M, Schlapbach, LJ, Anderson, S, Secka, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Kuijpers, TW, Martinon-Torres, F, Zenz, W, Levin, M, Hibberd, ML, Davila, S, Gormley, S, Hamilton, S, Herberg, J, Hourmat, B, Hoggart, C, Kaforou, M, Sancho-Shimizu, V, Abdulla, A, Agapow, P, Bartlett, M, Bellos, E, Eleftherohorinou, H, Galassini, R, Inwald, D, Mashbat, M, Menikou, S, Mustafa, S, Nadel, S, Rahman, R, Thakker, C, Bokhandi, S, Power, S, Barham, H, Pathan, N, Ridout, J, White, D, Thurston, S, Faust, S, Patel, S, McCorkell, J, Davies, P, Cratev, L, Navarra, H, Carter, S, Ramaiah, R, Patel, R, Tuffrey, C, Gribbin, A, McCready, S, Peters, M, Hardy, K, Standing, F, O'Neill, L, Abelake, E, Deep, A, Nsirim, E, Willis, L, Young, Z, Royad, C, White, S, Fortune, PM, Hudnott, P, Alvez Gonzalez, F, Barral-Arca, R, Cebey-Lopez, M, Jose Curras-Tuala, M, Garcia, N, Garcia Vicente, L, Gomez-Carballa, A, Gomez Rial, J, Grela Beiroa, A, Justicia Grande, A, Leborans Iglesias, P, Martinez Santos, AE, Martinon-Torres, N, Martinon Sanchez, JM, Mosquera Perez, B, Obando Pacheco, P, Pardo-Seco, J, Pischedda, S, Rivero Calle, I, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Seren Fernandez, S, Porto Silva, MDS, Vega, A, Beatriz Reyes, S, Leon Leon, MC, Navarro Mingorance, A, Gabaldo Barrios, X, Onate Vergara, E, Concha Torre, A, Vivanco, A, Fernandez, R, Gimenez Sanchez, F, Sanchez Forte, M, Rojo, P, Ruiz Contreras, J, Palacios, A, Navarro, M, Alvarez Alvarez, C, Jose Lozano, M, Carreras, E, Brio Sanagustin, S, Neth, O, Martinez Padilla, MDC, Prieto Tato, LM, Guillen, S, Fernandez Silveira, L, Moreno, D, van Furth, AMT, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Paulus, S, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Agbeko, R, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Saidykhan, M, Cole, F, Thomas, G, Antonio, M, Walcher, W, Geishofer, G, Klobassa, D, Martin, M, Pfurtscheller, K, Reiter, K, Roedl, S, Zobel, G, Zoehrer, B, Toepke, B, Fucik, P, Gabriel, M, Penzien, JM, Diab, G, Miething, R, Deeg, KH, Hammer, J, Varnholt, V, Schmidt, A, Bindl, L, Sillaber, U, Huemer, C, Meier, P, Simic-Schleicher, G, Markart, M, Pfau, E, Broede, H, Ausserer, B, Kalhoff, H, Arpe, V, Schweitzer-Krantz, S, Kasper, J-M, Loranth, K, Bittrich, HJ, Simma, B, Klinge, J, Fedlmaier, M, Weigand, N, Herting, E, Grube, R, Fusch, C, Gruber, A, Schimmel, U, Knaufer-Schiefer, S, Laessig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Mueller, H, Kurnik, P, Groneck, P, Weiss, U, Groeblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Goepel, W, Schulz, D, Berger, T, Hauser, E, Foerster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Hueseman, D, Schuermann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, H-L, Quietzach, J, Koenig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Goerke, W, Nossal, R, Pernice, W, Brangenberg, R, Salzer, HR, Koch, H, Schaller, G, Paky, F, Strasser, F, Eitelberger, F, Sontheimer, D, Lischka, A, Kronberger, M, Dilch, A, Scheibenpflug, C, Bruckner, R, Mahler, K, Runge, K, Kunze, W, Schermann, P, Borghini, L, Png, E, Binder, A, Wright, VJ, Pinnock, E, de Groot, R, Hazelzet, J, Emonts, M, Van der Flier, M, Schlapbach, LJ, Anderson, S, Secka, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Kuijpers, TW, Martinon-Torres, F, Zenz, W, Levin, M, Hibberd, ML, Davila, S, Gormley, S, Hamilton, S, Herberg, J, Hourmat, B, Hoggart, C, Kaforou, M, Sancho-Shimizu, V, Abdulla, A, Agapow, P, Bartlett, M, Bellos, E, Eleftherohorinou, H, Galassini, R, Inwald, D, Mashbat, M, Menikou, S, Mustafa, S, Nadel, S, Rahman, R, Thakker, C, Bokhandi, S, Power, S, Barham, H, Pathan, N, Ridout, J, White, D, Thurston, S, Faust, S, Patel, S, McCorkell, J, Davies, P, Cratev, L, Navarra, H, Carter, S, Ramaiah, R, Patel, R, Tuffrey, C, Gribbin, A, McCready, S, Peters, M, Hardy, K, Standing, F, O'Neill, L, Abelake, E, Deep, A, Nsirim, E, Willis, L, Young, Z, Royad, C, White, S, Fortune, PM, Hudnott, P, Alvez Gonzalez, F, Barral-Arca, R, Cebey-Lopez, M, Jose Curras-Tuala, M, Garcia, N, Garcia Vicente, L, Gomez-Carballa, A, Gomez Rial, J, Grela Beiroa, A, Justicia Grande, A, Leborans Iglesias, P, Martinez Santos, AE, Martinon-Torres, N, Martinon Sanchez, JM, Mosquera Perez, B, Obando Pacheco, P, Pardo-Seco, J, Pischedda, S, Rivero Calle, I, Rodriguez-Tenreiro, C, Redondo-Collazo, L, Seren Fernandez, S, Porto Silva, MDS, Vega, A, Beatriz Reyes, S, Leon Leon, MC, Navarro Mingorance, A, Gabaldo Barrios, X, Onate Vergara, E, Concha Torre, A, Vivanco, A, Fernandez, R, Gimenez Sanchez, F, Sanchez Forte, M, Rojo, P, Ruiz Contreras, J, Palacios, A, Navarro, M, Alvarez Alvarez, C, Jose Lozano, M, Carreras, E, Brio Sanagustin, S, Neth, O, Martinez Padilla, MDC, Prieto Tato, LM, Guillen, S, Fernandez Silveira, L, Moreno, D, van Furth, AMT, van der Flier, M, Boeddha, NP, Driessen, GJA, Pajkrt, D, Sanders, EAM, van de Beek, D, van der Ende, A, Philipsen, HLA, Adeel, AOA, Breukels, MA, Brinkman, DMC, de Korte, CCMM, de Vries, E, de Waal, WJ, Dekkers, R, Dings-Lammertink, A, Doedens, RA, Donker, AE, Dousma, M, Faber, TE, Gerrits, GPJM, Gerver, JAM, Heidema, J, Homan-van der Veen, J, Jacobs, MAM, Jansen, NJG, Kawczynski, P, Klucovska, K, Kneyber, MCJ, Koopman-Keemink, Y, Langenhorst, VJ, Leusink, J, Loza, BF, Merth, IT, Miedema, CJ, Neeleman, C, Noordzij, JG, Obihara, CC, van Overbeek-van Gils, ALT, Poortman, GH, Potgieter, ST, Potjewijd, J, Rosias, PPR, Sprong, T, ten Tussher, GW, Thio, BJ, Tramper-Stranders, GA, van Deuren, M, van der Meer, H, van Kuppevelt, AJM, van Wermeskerken, AM, Verwijs, WA, Wolfs, TFW, Agyeman, P, Aebi, C, Berger, C, Giannoni, E, Stocker, M, Posfay-Barbe, KM, Heininger, U, Bernhard-Stirnemann, S, Niederer-Loher, A, Kahlert, C, Hasters, P, Relly, C, Baer, W, Paulus, S, Frederick, H, Jennings, R, Johnston, J, Kenwright, R, Agbeko, R, Bojang, K, Sarr, I, Kebbeh, N, Sey, G, Saidykhan, M, Cole, F, Thomas, G, Antonio, M, Walcher, W, Geishofer, G, Klobassa, D, Martin, M, Pfurtscheller, K, Reiter, K, Roedl, S, Zobel, G, Zoehrer, B, Toepke, B, Fucik, P, Gabriel, M, Penzien, JM, Diab, G, Miething, R, Deeg, KH, Hammer, J, Varnholt, V, Schmidt, A, Bindl, L, Sillaber, U, Huemer, C, Meier, P, Simic-Schleicher, G, Markart, M, Pfau, E, Broede, H, Ausserer, B, Kalhoff, H, Arpe, V, Schweitzer-Krantz, S, Kasper, J-M, Loranth, K, Bittrich, HJ, Simma, B, Klinge, J, Fedlmaier, M, Weigand, N, Herting, E, Grube, R, Fusch, C, Gruber, A, Schimmel, U, Knaufer-Schiefer, S, Laessig, W, Hennenberger, A, von der Wense, A, Tillmann, R, Schwarick, J, Sitzmann, FC, Streif, W, Mueller, H, Kurnik, P, Groneck, P, Weiss, U, Groeblacher-Roth, H, Bensch, J, Moser, R, Schwarz, R, Lenz, K, Hofmann, T, Goepel, W, Schulz, D, Berger, T, Hauser, E, Foerster, KM, Peters, J, Nicolai, TH, Kumlien, B, Beckmann, R, Seitz, C, Hueseman, D, Schuermann, R, Ta, VH, Weikmann, E, Evert, W, Hautz, J, Seidenberg, J, Wocko, L, Luigs, P, Reiter, H-L, Quietzach, J, Koenig, M, Herrmann, J, Mitter, H, Seidler, E, Maak, B, Sperl, W, Zwiauer, K, Meissl, M, Koch, R, Cremer, M, Breuer, HA, Goerke, W, Nossal, R, Pernice, W, Brangenberg, R, Salzer, HR, Koch, H, Schaller, G, Paky, F, Strasser, F, Eitelberger, F, Sontheimer, D, Lischka, A, Kronberger, M, Dilch, A, Scheibenpflug, C, Bruckner, R, Mahler, K, Runge, K, Kunze, W, and Schermann, P
Abstract: Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
Published: 2019

34. Bacteremia in Childhood Life-Threatening Infections in Urban Gambia: EUCLIDS in West Africa

Author: MS Mondziekten/Kaakchirurgie, Infectieziekten patientenzorg, Secka, F, Herberg, J A, Sarr, I, Darboe, S, Sey, G, Saidykhan, M, Wathuo, M, Kaforou, M, Antonio, M, Roca, A, Zaman, S M A, Cebey-López, M, Boeddha, N P, Paulus, S, Kohlfürst, D S, Emonts, M, Zenz, W, Carrol, E D, de Groot, R, Schlapbach, L, Martinon-Torres, F, Bojang, K, Levin, M, van der Flier, M, Anderson, S T, MS Mondziekten/Kaakchirurgie, Infectieziekten patientenzorg, Secka, F, Herberg, J A, Sarr, I, Darboe, S, Sey, G, Saidykhan, M, Wathuo, M, Kaforou, M, Antonio, M, Roca, A, Zaman, S M A, Cebey-López, M, Boeddha, N P, Paulus, S, Kohlfürst, D S, Emonts, M, Zenz, W, Carrol, E D, de Groot, R, Schlapbach, L, Martinon-Torres, F, Bojang, K, Levin, M, van der Flier, M, and Anderson, S T
Published: 2019

35. Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Author: Wang, XZ, Nijman, R, Camuzeaux, S, Sands, C, Jackson, H, Kaforou, M, Boeddha, Navin, Driessen, Gertjan, Emonts, Marieke, Hazelzet, Jan, Ziuraite, I, Zukovskaja, V, Wang, XZ, Nijman, R, Camuzeaux, S, Sands, C, Jackson, H, Kaforou, M, Boeddha, Navin, Driessen, Gertjan, Emonts, Marieke, Hazelzet, Jan, Ziuraite, I, and Zukovskaja, V
Published: 2019

36. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice

Author: Rosello, M, Kaforou, M, Frontini, A, Okolo, A, Chan, Y-W, Nikolopoulou, E, Millership, S, Fenech, ME, MacIntyre, D, Turner, JO, Moore, JD, Blackburn, E, Gullick, WJ, Cinti, S, Montana, G, Parker, MG, and Christian, M
Subjects: adipokine, Adipose Tissue, White, Cold-Shock Response, brown adipose tissue, brite, Articles, Microarray Analysis, cold, PC12 Cells, Rats, Mice, Inbred C57BL, Mice, Adipose Tissue, Brown, Gene Expression Regulation, subcutaneous white adipose tissue, Animals, Female, Transcriptome, visceral white adipose tissue, Cells, Cultured
Abstract: Brown adipocytes dissipate energy, whereas white adipocytes are an energy storage site. We explored the plasticity of different white adipose tissue depots in acquiring a brown phenotype by cold exposure. By comparing cold-induced genes in white fat to those enriched in brown compared with white fat, at thermoneutrality we defined a "brite" transcription signature. We identified the genes, pathways, and promoter regulatory motifs associated with "browning," as these represent novel targets for understanding this process. For example, neuregulin 4 was more highly expressed in brown adipose tissue and upregulated in white fat upon cold exposure, and cell studies showed that it is a neurite outgrowth-promoting adipokine, indicative of a role in increasing adipose tissue innervation in response to cold. A cell culture system that allows us to reproduce the differential properties of the discrete adipose depots was developed to study depot-specific differences at an in vitro level. The key transcriptional events underpinning white adipose tissue to brown transition are important, as they represent an attractive proposition to overcome the detrimental effects associated with metabolic disorders, including obesity and type 2 diabetes.
Published: 2014
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37. Correction: Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children (vol 316, pg 835, 2016)

Author: Herberg, JA, Kaforou, M, and Wright, VJ
Subjects: Science & Technology, Medicine, General & Internal, General & Internal Medicine, 11 Medical And Health Sciences, Life Sciences & Biomedicine
Published: 2017

38. Childhood tuberculosis is associated with decreased abundance of T cell gene transcripts and impaired T cell function

Author: Rottenberg, ME, Hemingway, C, Berk, M, Anderson, ST, Wright, VJ, Hamilton, S, Eleftherohorinou, H, Kaforou, M, Goldgof, GM, Hickman, K, Kampmann, B, Schoeman, J, Eley, B, Beatty, D, Pienaar, S, Nicol, MP, Griffiths, MJ, Waddell, SJ, Newton, SM, Coin, LJ, Relman, DA, Montana, G, Levin, M, Rottenberg, ME, Hemingway, C, Berk, M, Anderson, ST, Wright, VJ, Hamilton, S, Eleftherohorinou, H, Kaforou, M, Goldgof, GM, Hickman, K, Kampmann, B, Schoeman, J, Eley, B, Beatty, D, Pienaar, S, Nicol, MP, Griffiths, MJ, Waddell, SJ, Newton, SM, Coin, LJ, Relman, DA, Montana, G, and Levin, M
Abstract: The WHO estimates around a million children contract tuberculosis (TB) annually with over 80 000 deaths from dissemination of infection outside of the lungs. The insidious onset and association with skin test anergy suggests failure of the immune system to both recognise and respond to infection. To understand the immune mechanisms, we studied genome-wide whole blood RNA expression in children with TB meningitis (TBM). Findings were validated in a second cohort of children with TBM and pulmonary TB (PTB), and functional T-cell responses studied in a third cohort of children with TBM, other extrapulmonary TB (EPTB) and PTB. The predominant RNA transcriptional response in children with TBM was decreased abundance of multiple genes, with 140/204 (68%) of all differentially regulated genes showing reduced abundance compared to healthy controls. Findings were validated in a second cohort with concordance of the direction of differential expression in both TBM (r2 = 0.78 p = 2x10-16) and PTB patients (r2 = 0.71 p = 2x10-16) when compared to a second group of healthy controls. Although the direction of expression of these significant genes was similar in the PTB patients, the magnitude of differential transcript abundance was less in PTB than in TBM. The majority of genes were involved in activation of leucocytes (p = 2.67E-11) and T-cell receptor signalling (p = 6.56E-07). Less abundant gene expression in immune cells was associated with a functional defect in T-cell proliferation that recovered after full TB treatment (p<0.0003). Multiple genes involved in T-cell activation show decreased abundance in children with acute TB, who also have impaired functional T-cell responses. Our data suggest that childhood TB is associated with an acquired immune defect, potentially resulting in failure to contain the pathogen. Elucidation of the mechanism causing the immune paresis may identify new treatment and prevention strategies.
Published: 2017

39. Diagnosis of Childhood Tuberculosis and Host RNA Expression in Africa

Author: Anderson, S.T., Kaforou, M., Brent, A.J., Wright, V.J., Banwell, C.M., Chagaluka, G., Crampin, A.C., Dockrell, H.M., French, N., Hamilton, M.S., Hibberd, M.L., Kern, F., Langford, P.R., Ling, L., Mlotha, R., Ottenhoff, T.H.M., Pienaar, S., Pillay, V., Scott, J.A.G., Twahir, H., Wilkinson, R.J., Coin, L.J., Heyderman, R.S., Levin, M., Eley, B., ILULU Consortium, and KIDS TB Study Grp
Subjects: Tuberculosis, biology, Latent tuberculosis, business.industry, Host (biology), 1. No poverty, wa_395, General Medicine, Disease, biology.organism_classification, medicine.disease, Article, 3. Good health, Mycobacterium tuberculosis, qu_58.7, Tuberculosis diagnosis, Immunology, wf_220, ws_280, Medicine, Population study, wf_200, Differential diagnosis, business
Abstract: Background\ud \ud Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV).\ud \ud Methods\ud \ud The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood.\ud \ud Results\ud \ud We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%.\ud \ud Conclusions\ud \ud RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).
Published: 2014

40. RIP140 represses the 'Brown-in-White' adipocyte program including a futile cycle of triacyclglycerol breakdown and synthesis

Author: Kiskinis, E, Chatzeli, L, Curry, E, Kaforou, M, Frontini, A, Cinti, S, Montana, G, Parker, MG, and Christian, M
Subjects: Male, Mice, Knockout, Mice, 129 Strain, Adipose Tissue, White, Nuclear Proteins, Cell Differentiation, Lipid Metabolism, Nuclear Receptor Interacting Protein 1, QR, Mice, Inbred C57BL, Mice, Adipocytes, Brown, Adipose Tissue, Brown, Animals, Female, Gene Silencing, Transcriptome, Cells, Cultured, Triglycerides, Original Research, Adaptor Proteins, Signal Transducing, Oligonucleotide Array Sequence Analysis
Abstract: Receptor-interacting protein 140 (RIP140) is a corepressor of nuclear receptors that is highly expressed in adipose tissues. We investigated the role of RIP140 in conditionally immortal preadipocyte cell lines prepared from white or brown fat depots. In white adipocytes, a large set of brown fat-associated genes was up-regulated in the absence of RIP140. In contrast, a relatively minor role can be ascribed to RIP140 in the control of basal gene expression in differentiated brown adipocytes because significant changes were observed only in Ptgds and Fabp3. The minor role of RIP140 in brown adipocytes correlates with the similar histology and uncoupling protein 1 and CIDEA staining in knockout compared with wild-type brown adipose tissue (BAT). In contrast, RIP140 knockout sc white adipose tissue (WAT) shows increased numbers of multilocular adipocytes with elevated staining for uncoupling protein 1 and CIDEA. Furthermore in a white adipocyte cell line, the markers of BRITE adipocytes, Tbx1, CD137, Tmem26, Cited1, and Epsti1 were repressed in the presence of RIP140 as was Prdm16. Microarray analysis of wild-type and RIP140-knockout white fat revealed elevated expression of genes associated with cold-induced expression or high expression in BAT. A set of genes associated with a futile cycle of triacylglycerol breakdown and resynthesis and functional assays revealed that glycerol kinase and glycerol-3-phosphate dehydrogenase activity as well as [(3)H]glycerol incorporation were elevated in the absence of RIP140. Thus, RIP140 blocks the BRITE program in WAT, preventing the expression of brown fat genes and inhibiting a triacylglycerol futile cycle, with important implications for energy homeostasis.
Published: 2014

41. A nucleic acid strand displacement system for the multiplexed detection of tuberculosis-specific mRNA using quantum dots

Author: Gliddon, H. D., primary, Howes, P. D., additional, Kaforou, M., additional, Levin, M., additional, and Stevens, M. M., additional
Published: 2016
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42. Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study

Author: Cattamanchi, A, Kaforou, M, Wright, VJ, Oni, T, French, N, Anderson, ST, Bangani, N, Banwell, C, Brent, AJ, Crampin, AC, Dockrell, HM, Eley, B, Heyderman, RS, Hibberd, ML, Kern, F, Langford, PR, Ling, L, Mendelson, M, Ottenhoff, TH, Zgambo, F, Wilkinson, RJ, Coin, LJ, Levin, M, Cattamanchi, A, Kaforou, M, Wright, VJ, Oni, T, French, N, Anderson, ST, Bangani, N, Banwell, C, Brent, AJ, Crampin, AC, Dockrell, HM, Eley, B, Heyderman, RS, Hibberd, ML, Kern, F, Langford, PR, Ling, L, Mendelson, M, Ottenhoff, TH, Zgambo, F, Wilkinson, RJ, Coin, LJ, and Levin, M
Abstract: BACKGROUND: A major impediment to tuberculosis control in Africa is the difficulty in diagnosing active tuberculosis (TB), particularly in the context of HIV infection. We hypothesized that a unique host blood RNA transcriptional signature would distinguish TB from other diseases (OD) in HIV-infected and -uninfected patients, and that this could be the basis of a simple diagnostic test. METHODS AND FINDINGS: Adult case-control cohorts were established in South Africa and Malawi of HIV-infected or -uninfected individuals consisting of 584 patients with either TB (confirmed by culture of Mycobacterium tuberculosis [M.TB] from sputum or tissue sample in a patient under investigation for TB), OD (i.e., TB was considered in the differential diagnosis but then excluded), or healthy individuals with latent TB infection (LTBI). Individuals were randomized into training (80%) and test (20%) cohorts. Blood transcriptional profiles were assessed and minimal sets of significantly differentially expressed transcripts distinguishing TB from LTBI and OD were identified in the training cohort. A 27 transcript signature distinguished TB from LTBI and a 44 transcript signature distinguished TB from OD. To evaluate our signatures, we used a novel computational method to calculate a disease risk score (DRS) for each patient. The classification based on this score was first evaluated in the test cohort, and then validated in an independent publically available dataset (GSE19491). In our test cohort, the DRS classified TB from LTBI (sensitivity 95%, 95% CI [87-100]; specificity 90%, 95% CI [80-97]) and TB from OD (sensitivity 93%, 95% CI [83-100]; specificity 88%, 95% CI [74-97]). In the independent validation cohort, TB patients were distinguished both from LTBI individuals (sensitivity 95%, 95% CI [85-100]; specificity 94%, 95% CI [84-100]) and OD patients (sensitivity 100%, 95% CI [100-100]; specificity 96%, 95% CI [93-100]). Limitations of our study include the use of only culture co
Published: 2013

43. Bioinformatics: living on the edge

Author: Bellos, E, Coin, LJM, Kaforou, M, Bellos, E, Coin, LJM, and Kaforou, M
Abstract: A report on the 11th European Conference on Computational Biology (ECCB), Basel, Switzerland, September 9-12, 2012.
Published: 2012

44. Diagnostic Test Accuracy of a 2-Transcript Host RNA Signature for Discriminating Bacterial vs Viral Infection in Febrile Children

Author: Herberg, JA, Kaforou, M, Wright, VJ, Shailes, H, Eleftherohorinou, H, Hoggart, CJ, Cebey-López, M, Carter, MJ, Janes, VA, Gormley, S, Shimizu, C, Tremoulet, AH, Barendregt, AM, Salas, A, Kanegaye, J, Pollard, AJ, Faust, SN, Patel, S, Kuijpers, T, Martinón-Torres, F, Burns, JC, Coin, LJM, Levin, M, and IRIS Consortium
Subjects: Genetic Markers, Male, Risk, Fever, Coinfection, Gene Expression Profiling, Infant, Bacterial Infections, Sensitivity and Specificity, Severity of Illness Index, 3. Good health, Anti-Bacterial Agents, Diagnosis, Differential, Cytoskeletal Proteins, Logistic Models, Virus Diseases, Area Under Curve, Child, Preschool, Humans, RNA, Female, Prospective Studies, Antigens, Biomarkers
Abstract: Importance: Because clinical features do not reliably distinguish bacterial from viral infection, many children worldwide receive unnecessary antibiotic treatment, while bacterial infection is missed in others. Objective: To identify a blood RNA expression signature that distinguishes bacterial from viral infection in febrile children. Design, Setting, and Participants: Febrile children presenting to participating hospitals in the United Kingdom, Spain, the Netherlands, and the United States between 2009-2013 were prospectively recruited, comprising a discovery group and validation group. Each group was classified after microbiological investigation as having definite bacterial infection, definite viral infection, or indeterminate infection. RNA expression signatures distinguishing definite bacterial from viral infection were identified in the discovery group and diagnostic performance assessed in the validation group. Additional validation was undertaken in separate studies of children with meningococcal disease (n = 24) and inflammatory diseases (n = 48) and on published gene expression datasets. Exposures: A 2-transcript RNA expression signature distinguishing bacterial infection from viral infection was evaluated against clinical and microbiological diagnosis. Main Outcomes and Measures: Definite bacterial and viral infection was confirmed by culture or molecular detection of the pathogens. Performance of the RNA signature was evaluated in the definite bacterial and viral group and in the indeterminate infection group. Results: The discovery group of 240 children (median age, 19 months; 62% male) included 52 with definite bacterial infection, of whom 36 (69%) required intensive care, and 92 with definite viral infection, of whom 32 (35%) required intensive care. Ninety-six children had indeterminate infection. Analysis of RNA expression data identified a 38-transcript signature distinguishing bacterial from viral infection. A smaller (2-transcript) signature (FAM89A and IFI44L) was identified by removing highly correlated transcripts. When this 2-transcript signature was implemented as a disease risk score in the validation group (130 children, with 23 definite bacterial, 28 definite viral, and 79 indeterminate infections; median age, 17 months; 57% male), all 23 patients with microbiologically confirmed definite bacterial infection were classified as bacterial (sensitivity, 100% [95% CI, 85%-100%]) and 27 of 28 patients with definite viral infection were classified as viral (specificity, 96.4% [95% CI, 89.3%-100%]). When applied to additional validation datasets from patients with meningococcal and inflammatory diseases, bacterial infection was identified with a sensitivity of 91.7% (95% CI, 79.2%-100%) and 90.0% (95% CI, 70.0%-100%), respectively, and with specificity of 96.0% (95% CI, 88.0%-100%) and 95.8% (95% CI, 89.6%-100%). Of the children in the indeterminate groups, 46.3% (63/136) were classified as having bacterial infection, although 94.9% (129/136) received antibiotic treatment. Conclusions and Relevance: This study provides preliminary data regarding test accuracy of a 2-transcript host RNA signature discriminating bacterial from viral infection in febrile children. Further studies are needed in diverse groups of patients to assess accuracy and clinical utility of this test in different clinical settings.

45. Evaluation of Phoenix Sepsis Score Criteria: Exploratory Analysis of Characteristics and Outcomes in an Emergency Transport PICU Cohort From the United Kingdom, 2014-2016.

Author: Carter MJ, Hageman J, Feinstein Y, Herberg J, Kaforou M, Peters MJ, Nadel S, Edmonds N, Pathan N, Levin M, and Ramnarayan P
Subjects: Humans, Retrospective Studies, Infant, Child, Preschool, Child, Male, Female, Adolescent, Infant, Newborn, United Kingdom epidemiology, Transportation of Patients statistics & numerical data, Hospital Mortality, Severity of Illness Index, Shock, Septic diagnosis, Shock, Septic mortality, Intensive Care Units, Pediatric statistics & numerical data, Sepsis diagnosis, Sepsis mortality, Sepsis epidemiology
Abstract: Objectives: To assess characteristics and outcomes of children with suspected or confirmed infection requiring emergency transport and PICU admission and to explore the association between the 2024 Phoenix Sepsis Score (PSS) criteria and mortality., Design: Retrospective analysis of curated data from a 2014-2016 multicenter cohort study., Setting: PICU admission following emergency transport in South East England, United Kingdom, from April 2014 to December 2016., Patients: Children 0-16 years old ( n = 663) of whom 444 (67%) had suspected or confirmed infection., Interventions: None., Measurements and Main Results: The PSS was calculated as a sum of four individual organ subscores (respiratory, cardiovascular, neurological, and coagulation) using the worst values during transport (i.e., from referral until the time of PICU admission). A score cutoff of greater than or equal to 2 points was used to define sepsis; and septic shock was defined as sepsis plus 1 or more cardiovascular subscore points. Sepsis occurred in 260 of 444 children (58.6%) with suspected or confirmed infection, with septic shock occurring in 177 of 260 (68.1%) of those with sepsis. A PSS score greater than or equal to 2 points occurred in 37 of 67 bronchiolitis cases, 19 of 35 meningoencephalitis cases, 30 of 47 pneumonia/empyema cases, 38 of 46 septic/toxic shock cases, nine of 15 severe sepsis cases, and 58 of 118 definite viral infections. Overall, 14 of 444 children died (3.2%). There were 12 deaths in the 260 children with PSS greater than or equal to 2, and two deaths in the 184 children with PSS less than 2 (4.6% vs. 1.1%; absolute difference, 3.5%; 95% CI, 0.1-6.9%; p = 0.04)., Conclusions: In 2014-2016, over half of the critically ill children undergoing emergency transport to PICU with presumed or confirmed infection, and meeting retrospectively applied PSS criteria for sepsis, had a range of clinical diagnoses including bronchiolitis, meningoencephalitis, and pneumonia/empyema. Furthermore, the PSS criteria for categorization of sepsis and septic shock were associated with outcome and may be of value in future risk-stratification in clinical trials., Competing Interests: Drs. Hageman, Herberg, and Ramnarayan received support for article research from the Great Ormond Street Hospital Children’s Charity. Dr. Peters’ institution received funding from the National Institute for Health and Care Research (NIHR), United Kingdom; he received support for article research from the NIHR, United Kingdom. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2025 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)
Published: 2025
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46. A diagnostic host-specific transcriptome response for Mycoplasma pneumoniae pneumonia to guide pediatric patient treatment.

Author: Viz-Lasheras S, Gómez-Carballa A, Bello X, Rivero-Calle I, Dacosta AI, Kaforou M, Habgood-Coote D, Cunnington AJ, Emonts M, Herberg JA, Wright VJ, Carrol ED, Paulus SC, Zenz W, Kohlfürst DS, Schweintzger N, Van der Flier M, de Groot R, Schlapbach LJ, Agyeman P, Pollard AJ, Fink C, Kuijpers TT, Anderson S, Von Both U, Pokorn M, Zavadska D, Tsolia M, Moll HA, Vermont C, Levin M, Martinón-Torres F, and Salas A
Subjects: Humans, Child, Child, Preschool, Female, Male, Anti-Bacterial Agents therapeutic use, Anti-Bacterial Agents pharmacology, Adolescent, Gene Expression Profiling methods, Infant, Pneumonia, Viral virology, Pneumonia, Viral diagnosis, Pneumonia, Viral drug therapy, Pneumonia, Mycoplasma drug therapy, Pneumonia, Mycoplasma microbiology, Pneumonia, Mycoplasma diagnosis, Pneumonia, Mycoplasma genetics, Mycoplasma pneumoniae genetics, Mycoplasma pneumoniae isolation & purification, Transcriptome genetics
Abstract: Mycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84-0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)
Published: 2025
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47. A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia.

Author: Viz-Lasheras S, Gómez-Carballa A, Pardo-Seco J, Bello X, Rivero-Calle I, Dacosta AI, Kaforou M, Habgood-Coote D, Cunnington AJ, Emonts M, Herberg JA, Wright VJ, Carrol ED, Paulus SC, Zenz W, Kohlfürst DS, Van der Flier M, de Groot R, Schlapbach LJ, Agyeman P, Pollard AJ, Fink C, Kuijpers TT, Anderson S, Calvo C, Martínez-Padilla MDC, Pérez-Aragón A, Gómez-Sánchez E, Valencia-Ramos J, Giménez-Sánchez F, Alonso-Quintela P, Moreno-Galarraga L, von Both U, Pokorn M, Zavadska D, Tsolia M, Vermont CL, Moll HA, Levin M, Martinón-Torres F, and Salas A
Abstract: Pneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A , BAG3 , TDRD9 , MXRA7 , and KLF14 ) that effectively distinguishes bacterial from viral pneumonia (area under the curve (AUC): 0.95 [0.88-1.00]). Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77-0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83-1.00]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments and potentially transforming clinical practice., Competing Interests: The authors have a European patent application related to this work under the identification number EP24382240., (© 2025 The Author(s).)
Published: 2025
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48. Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).

Author: Bellos E, Santillo D, Vantourout P, Jackson HR, Duret A, Hearn H, Seeleuthner Y, Talouarn E, Hodeib S, Patel H, Powell O, Yeoh S, Mustafa S, Habgood-Coote D, Nichols S, Estramiana Elorrieta L, D'Souza G, Wright VJ, Estrada-Rivadeneyra D, Tremoulet AH, Dummer KB, Netea SA, Condino-Neto A, Lau YL, Núñez Cuadros E, Toubiana J, Holanda Pena M, Rieux-Laucat F, Luyt CE, Haerynck F, Mège JL, Chakravorty S, Haddad E, Morin MP, Metin Akcan Ö, Keles S, Emiroglu M, Alkan G, Tüter Öz SK, Elmas Bozdemir S, Morelle G, Volokha A, Kendir-Demirkol Y, Sözeri B, Coskuner T, Yahsi A, Gulhan B, Kanik-Yuksek S, Bayhan GI, Ozkaya-Parlakay A, Yesilbas O, Hatipoglu N, Ozcelik T, Belot A, Chopin E, Barlogis V, Sevketoglu E, Menentoglu E, Gayretli Aydin ZG, Bloomfield M, AlKhater SA, Cyrus C, Stepanovskiy Y, Bondarenko A, Öz FN, Polat M, Fremuth J, Lebl J, Geraldo A, Jouanguy E, Carter MJ, Wellman P, Peters M, Pérez de Diego R, Edwards LA, Chiu C, Noursadeghi M, Bolze A, Shimizu C, Kaforou M, Hamilton MS, Herberg JA, Schmitt EG, Rodriguez-Palmero A, Pujol A, Kim J, Cobat A, Abel L, Zhang SY, Casanova JL, Kuijpers TW, Burns JC, Levin M, Hayday AC, and Sancho-Shimizu V
Subjects: Humans, Child, Male, Female, Child, Preschool, Heterozygote, Adolescent, Genetic Predisposition to Disease, Infant, COVID-19 genetics, COVID-19 complications, COVID-19 immunology, COVID-19 virology, Systemic Inflammatory Response Syndrome genetics, Butyrophilins genetics, Butyrophilins metabolism, SARS-CoV-2
Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, "burdenMC," which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2., (© 2024 Bellos et al.)
Published: 2024
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49. SARS-CoV-2 human challenge reveals biomarkers that discriminate early and late phases of respiratory viral infections.

Author: Rosenheim J, Gupta RK, Thakker C, Mann T, Bell LCK, Broderick CM, Madon K, Papargyris L, Dayananda P, Kwok AJ, Greenan-Barrett J, Wagstaffe HR, Conibear E, Fenn J, Hakki S, Lindeboom RGH, Dratva LM, Lemetais B, Weight CM, Venturini C, Kaforou M, Levin M, Kalinova M, Mann AJ, Catchpole A, Knight JC, Nikolić MZ, Teichmann SA, Killingley B, Barclay W, Chain BM, Lalvani A, Heyderman RS, Chiu C, and Noursadeghi M
Subjects: Humans, Male, Respiratory Tract Infections virology, Respiratory Tract Infections diagnosis, Female, Adult, Membrane Proteins metabolism, Membrane Proteins genetics, Middle Aged, Rhinovirus genetics, Influenza, Human virology, Influenza, Human diagnosis, Influenza, Human blood, COVID-19 virology, COVID-19 diagnosis, Biomarkers blood, Biomarkers metabolism, SARS-CoV-2 genetics, Myxovirus Resistance Proteins genetics, Myxovirus Resistance Proteins metabolism, Viral Load
Abstract: Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27, shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing., Competing Interests: Competing interests: The Authors declare the following competing interests: In the past 3 years, S.A.T. has received remuneration for scientific advisory board membership from Sanofi, GlaxoSmithKline, Foresite Labs and Qiagen. S.A.T. is a co-founder and holds equity in Transition Bio and Ensocell. From 8 January 2024, S.A.T. has been a part-time employee of GlaxoSmithKline. A.J.M., A.C., M.K., M.M. and A.B. are full time employees at hVIVO Services Ltd. No other authors report any competing interests., (© 2024. The Author(s).)
Published: 2024
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50. Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome.

Author: Camino-Mera A, Pardo-Seco J, Bello X, Argiz L, Boyle RJ, Custovic A, Herberg J, Kaforou M, Arasi S, Fiocchi A, Pecora V, Barni S, Mori F, Bracamonte T, Echeverria L, O'Valle-Aísa V, Hernández-Martínez NL, Carballeira I, García E, Garcia-Magan C, Moure-González JD, Gonzalez-Delgado P, Garriga-Baraut T, Infante S, Zambrano-Ibarra G, Tomás-Pérez M, Machinena A, Pascal M, Prieto A, Vázquez-Cortes S, Fernández-Rivas M, Vila L, Alsina L, Torres MJ, Mangone G, Quirce S, Martinón-Torres F, Vázquez-Ortiz M, Gómez-Carballa A, and Salas A
Subjects: Humans, Male, Female, Infant, Child, Preschool, Genetic Predisposition to Disease, Filaggrin Proteins, Child, Allergens immunology, Genome-Wide Association Study, Enterocolitis genetics, Enterocolitis immunology, Enterocolitis diagnosis, Exome Sequencing, Food Hypersensitivity genetics, Food Hypersensitivity immunology, Food Hypersensitivity diagnosis, Biomarkers
Abstract: Background: Food protein-induced enterocolitis syndrome (FPIES) is a food allergy primarily affecting infants, often leading to vomiting and shock. Due to its poorly understood pathophysiology and lack of specific biomarkers, diagnosis is frequently delayed. Understanding FPIES genetics can shed light on disease susceptibility and pathophysiology-key to developing diagnostic, prognostic, preventive and therapeutic strategies. Using a well-characterised cohort of patients we explored the potential genome-wide susceptibility factors underlying FPIES., Methods: Blood samples from 41 patients with oral food challenge-proven FPIES were collected for a comprehensive whole exome sequencing association study., Results: Notable genetic variants, including rs872786 (RBM8A), rs2241880 (ATG16L1) and rs2289477 (ATG16L1), were identified as significant findings in FPIES. A weighted SKAT model identified six other associated genes including DGKZ and SIRPA. DGKZ induces TGF-β signalling, crucial for epithelial barrier integrity and IgA production; RBM8A is associated with thrombocytopenia absent radius syndrome, frequently associated with cow's milk allergy; SIRPA is associated with increased neutrophils/monocytes in inflamed tissues as often observed in FPIES; ATG16L1 is associated with inflammatory bowel disease. Coexpression correlation analysis revealed a functional correlation between RBM8A and filaggrin gene (FLG) in stomach and intestine tissue, with filaggrin being a known key pathogenic and risk factor for IgE-mediated food allergy. A transcriptome-wide association study suggested genetic variability in patients impacted gene expression of RBM8A (stomach and pancreas) and ATG16L1 (transverse colon)., Conclusions: This study represents the first case-control exome association study of FPIES patients and marks a crucial step towards unravelling genetic susceptibility factors underpinning the syndrome. Our findings highlight potential factors and pathways contributing to FPIES, including epithelial barrier dysfunction and immune dysregulation. While these results are novel, they are preliminary and need further validation in a second cohort of patients., (© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)
Published: 2024
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