Molecular Pathogen Testing for Identifying the Etiology of Febrile Illness in Immunocompromised Children

Author(s): Fabian JS van der Velden, Priyen Shah, Marie Voice, Emma Lim, Jethro Herberg, Victoria Wright, Tisham De, Enitan D. Carrol, Aakash Khanijau, Andrew J Pollard, Stéphane Paulus, Ulrich von Both, Laura Kolberg, Clementien L Vermont, Nienke N Hagedoorn, Federico Martinón-Torres, Irene Rivero Calle, Philipp KA Agyeman, Luregn J Schlapbach, Maria Tsolia, Irini Eleftheriou, Marko Pokorn, Mojca Kolnik, Taco W Kuijpers, Dace Zavadska, Aleksandra Rudzate, Nina A Schweintzger, Werner Zenz,

Background: Diagnosing febrile illness in immunocompromised children at presentation to hospital remains a challenge. Serious bacterial infection can cause significant mortality and morbidity, but conventional diagnostics using culture-based technology results are often negative. Molecular pathogen testing might increase the yield of pathogen detection in this population, subsequently potentially altering clinical management and improving outcome.

Methods: Immunocompromised febrile children recruited to the international Personalised Risk assessment in Febrile illness to Optimised Real-life Management study (PERFORM) were evaluated using current best practice local diagnostic approaches, and subsequently assigned to phenotypes based on standardized definitions. Retrospectively, these febrile cases were complemented by additional centralized molecular tests (CMT) for 22 respiratory and 35 blood pathogens and subsequently we analyzed febrile cases using CMT and local microbiological data. Results: There were 336 febrile episodes, of which 45 definite bacterial (13.4%), 37 definite viral (11.0%) using conventional diagnostic approaches, and 254 with more uncertain or inflammatory etiologies of fever (75.6%), and 54 non-febrile control cases. CMT detected any pathogens in 201/336 febrile cases (59.8%) and 33/54 non-febrile controls (61.1%). CMT detected E. cloacae, Enterobacteriales, and K. pneumoniae more commonly in definite bacterial cases compared to other febrile cases. There were no pathogens significantly more often detected in febrile cases versus controls, nor were any viral pathogens more often detected in definite viral cases by CMT. Bacterial pathogen detection was seen more often in definite bacterial cases on CMT (odds ratio 20.71 (95% confidence interval 2.11-203.77)). Viruses were detected in 46.7% of definite bacterial cases (N= 21), and 57.4% of controls (N= 31). Bacteria were detected in 10.8% of definite viral cases (N= 4), and 5.6% of controls (N=3). Human herpes virus (HHV)7 was equally the most commonly detected pathogen across all phenotypes (33.6%, N=113) in respectively 22.2% of definite bacterial (N=10), 32.4% of definite viral (N=12), and 36.4% of unknown bacterial or viral febrile illness (N=43) and controls (37.0%, N=20).

Conclusion: CMT frequently detected pathogens in both febrile children and non-febrile controls. Except for certain gram-negative bacteria, no pathogens were more commonly detected in definite bacterial or definite viral febrile illness. Viruses are detected in a significant proportion of patients with bacterial infection. HHV7 is frequently detected in immunocompromised children, both febrile and non-febrile. CMT can increase detection of pathogens, but our data do not suggest it will ease the current diagnostic challenges regarding their clinical relevance in this population.

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