Febrile illness in high-risk children: a prospective, international observational study
Authors: van der Velden Fabian J. S. , de Vries Gabriella , Martin Alexander , Lim Emma , von Both Ulrich , Kolberg Laura , Carrol Enitan D. , Khanijau Aakash , Herberg Jethro A. , De Tisham , Galassini Rachel , Kuijpers Taco W. , Martinón-Torres Federico , Rivero-Calle Irene , Vermont Clementien L. , Hagedoorn Nienke N. , Pokorn Marko , Pollard Andrew J. , Schlapbach Luregn J. , Tsolia Maria , Elefhteriou Irini , Yeung Shunmay , Zavadska Dace , Fink Colin , Voice Marie , Zenz Werner , Kohlmaier Benno , Agyeman Philipp K. A. , Usuf Effua , Secka Fatou , de Groot Ronald , Levin Michael , van der Flier Michiel , Emonts Marieke ,   PERFORM consortium, Levin Michael , Cunnington Aubrey , De Tisham , Herberg Jethro , Kaforou Myrsini , Wright Victoria , Baumard Lucas , Bellos Evangelos , D’Souza Giselle , Galassini Rachel , Habgood-Coote Dominic , Hamilton Shea , Hoggart Clive , Hourmat Sara , Jackson Heather , Maconochie Ian , Menikou Stephanie , Lin Naomi , Nichols Samuel , Nijman Ruud , Powell Oliver , Pena Paz Ivonne , Shah Priyen , Shen Ching-Fen , Vito Ortensia , Wilson Clare , Abdulla Amina , Ali Ladan , Darnell Sarah , Jorgensen Rikke , Mustafa Sobia , Persand Salina , Stevens Molly M. , Kim Nayoung , Kim Eunjung , Fidler Katy , Dudley Julia , Richmond Vivien , Tavliavini Emma , Shen Ching-Fen , Liu Ching-Chuan , Wang Shih-Min , Martinón-Torres Federico , Salas Antonio , Álvez González Fernando , Balo Farto Cristina , Barral-Arca Ruth , Barreiro Castro María , Bello Xabier , García Mirian Ben , Carnota Sandra , Cebey-López Miriam , Curras-Tuala María José , Durán Suárez Carlos , García Vicente Luisa , Gómez-Carballa Alberto , Gómez Rial Jose , Leboráns Iglesias Pilar , Martinón-Torres Federico , Martinón-Torres Nazareth , Martinón Sánchez José María , Mosquera Pérez Belén , Pardo-Seco Jacobo , Rodríguez Lidia Piñeiro , Pischedda Sara , Vázquez Sara Rey , Rivero Calle Irene , Rodríguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Sadiki Ora Miguel , Salas Antonio , Serén Fernández Sonia , Serén Trasorras Cristina , Vilas Iglesias Marisol , Zavadska Dace , Balode Anda , Bārzdiņa Arta , Deksne Dārta , Gardovska Dace , Grāvele Dagne , Grope Ilze , Meiere Anija , Nokalna Ieva , Pavāre Jana , Pučuka Zanda , Selecka Katrīna , Rudzāte Aleksandra , Svile Dace , Urbāne Urzula Nora , Usuf Effua , Bojang Kalifa , Zaman Syed M. A. , Secka Fatou , Anderson Suzanne , RocaIsatou Sarr Anna , Saidykhan Momodou , Darboe Saffiatou , Ceesay Samba , D’alessandro Umberto , Moll Henriëtte A. , Vermont Clementien L , Borensztajn Dorine M. , Hagedoorn Nienke N. , Tan Chantal , Zachariasse Joany , Dik W , Agyeman Philipp KA , Berger Christoph , Giannoni Eric , Stocker Martin , Posfay-Barbe Klara M , Heininger Ulrich , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian R. , Natalucci Giancarlo , Relly Christa , Riedel Thomas , Aebi Christoph , Schlapbach Luregn J , Carrol Enitan D , Cocklin Elizabeth , Jennings Rebecca , Johnston Joanne , Khanijau Aakash , Leigh Simon , Lewis-Burke Nadia , Newall Karen , Romaine Sam , Tsolia Maria , Eleftheriou Irini , Tambouratzi Maria , Marmarinos Antonis , Xagorari Marietta , Syggelou Kelly , Fink Colin , Voice Marie , Calvo-Bado Leo , Zenz Werner , Kohlmaier Benno , Schweintzger Nina A. , Sagmeister Manfred G. , Kohlfürst Daniela S. , Zurl Christoph , Binder Alexander , Hösele Susanne , Leitner Manuel , Pölz Lena , Rajic Glorija , Bauchinger Sebastian , Baumgart Hinrich , Benesch Martin , Ceolotto Astrid , Eber Ernst , Gallistl Siegfried , Gores Gunther , Haidl Harald , Hauer Almuthe , Hude Christa , Keldorfer Markus , Krenn Larissa , Pilch Heidemarie , Pfleger Andreas , Pfurtscheller Klaus , Nordberg Gudrun , Niedrist Tobias , Rödl Siegfried , Skrabl-Baumgartner Andrea , Sperl Matthias , Stampfer Laura , Strenger Volker , Till Holger , Trobisch Andreas , Löffler Sabine , Yeung Shunmay , Dewez Juan Emmanuel , Hibberd Martin , Bath David , Miners Alec , Nijman Ruud , Fitchett Elizabeth , de Groot Ronald , van der Flier Michiel , de Jonge Marien I. , van Aerde Koen , Alkema Wynand , van den Broek Bryan , Gloerich Jolein , van Gool Alain J. , Henriet Stefanie , Huijnen Martijn , Philipsen Ria , Willems Esther , Gerrits G.P.J.M. , van Leur M. , Heidema J. , de Haan L. , Miedema C.J. , Neeleman C. , Obihara C.C. , Tramper-Stranders G.A. , Pollard Andrew J. , Kandasamy Rama , Paulus Stéphane , Carter Michael J. , O’Connor Daniel , Bibi Sagida , Kelly Dominic F. , Gurung Meeru , Thorson Stephen , Ansari Imran , Murdoch David R. , Shrestha Shrijana , Oliver Zoe , Emonts Marieke , Lim Emma , Valentine Lucille , Allen Karen , Bell Kathryn , Chan Adora , Crulley Stephen , Devine Kirsty , Fabian Daniel , King Sharon , McAlinden Paul , McDonald Sam , McDonnell Anne , Pickering Ailsa , Thomson Evelyn , Wood Amanda , Wallia Diane , Woodsford Phil , Baxter Frances , Bell Ashley , Rhodes Mathew , Agbeko Rachel , Mackerness Christine , Baas Bryan , Kloosterhuis Lieke , Oosthoek Wilma , Arif Tasnim , Bennet Joshua , Collings Kalvin , van der Giessen Ilona , Martin Alex , Rashid Aqeela , Rowlands Emily , de Vries Gabriella , van der Velden Fabian , Soon Joshua , Valentine Lucille , Martin Mike , Mistry Ravi , von Both Ulrich , Kolberg Laura , Zwerenz Manuela , Buschbeck Judith , Bidlingmaier Christoph , Binder Vera , Danhauser Katharina , Haas Nikolaus , Griese Matthias , Feuchtinger Tobias , Keil Julia , Kappler Matthias , Lurz Eberhard , Muench Georg , Reiter Karl , Schoen Carola , Mallet François , Brengel-Pesce Karen , Pachot Alexandre , Mommert Marine , Pokorn Marko , Kolnik Mojca , Vincek Katarina , Srovin Tina Plankar , Bahovec Natalija , Prunk Petra , Osterman Veronika , Avramoska Tanja , Kuijpers Taco , Jongerius Ilse , van den Berg J. M. , Schonenberg D. , Barendregt A. M. , Pajkrt D. , van der Kuip M. , van Furth A. M. , Sprenkeler Evelien , Zandstra Judith , van Mierlo G. , Geissler J. 
Published: October 2022

To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the ‘Biomarker Validation in HR patients’ database in PERFORM, were analysed. Immunocompromised children (< 18 years old) presented to fifteen European hospitals in nine countries, and one Gambian hospital, with fever or suspected infection and clinical indication for blood investigations. Febrile episodes were assigned clinical phenotypes using the validated PERFORM algorithm. Logistic regression was used to assess the effect size of predictive features of proven/presumed bacterial or viral infection. A total of 599 episodes in 482 children were analysed. Seventy-eight episodes (13.0%) were definite bacterial, 67 episodes probable bacterial (11.2%), and 29 bacterial syndrome (4.8%). Fifty-five were definite viral (9.2%), 49 probable viral (8.2%), and 23 viral syndrome (3.8%). One hundred ninety were unknown bacterial or viral infections (31.7%), and 108 had inflammatory or other non-infectious causes of fever (18.1%). Predictive features of proven/presumed bacterial infection were ill appearance (OR 3.1 (95% CI 2.1–4.6)) and HIV (OR 10.4 (95% CI 2.0–54.4)). Ill appearance reduced the odds of having a proven/presumed viral infection (OR 0.5 (95% CI 0.3–0.9)). A total of 82.1% had new empirical antibiotics started on admission (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522).

   Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population.

What is Known:• Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom.• Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low.

What is New:• Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective.• The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers.