MR-Pro-adrenomedullin (MR-proADM) and Host Immune Response Biomarkers Evaluation of procalcitonin-guided antibiotic duration in Children with Infection for Stratification of Effectiveness: the PRECISE Study

Background The host-response to bacterial infection is highly heterogeneous; there is therefore a need for stratified treatment strategies instead of the traditional ‘one-size-fits-all’ approach. A precision medicine approach can improve patient outcomes by identifying endotypes in whom an intervention is likely to be beneficial, harmful or ineffective. Aim/objective To embed, within the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial, a mechanistic sub-study to determine endotypes of endothelial dysfunction using mid-regional proadrenomedullin and based on host immune response biomarkers tumour necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein 10 and C-reactive protein in whom a procalcitonin-guided antibiotic algorithm might be (a) particularly beneficial, (b) ineffective, or (c) harmful. To determine, within the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial, if there were specific sub-groups of patients (based on host response and organ dysfunction) in whom the addition of procalcitonin testing to current best practice based on the National Institute for Health and Care Excellence antimicrobial stewardship guidelines could safely allow a reduction in duration of antibiotic therapy in hospitalised children with suspected or confirmed bacterial infection compared to current best practice alone. Design Mechanism of action study embedded into the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection randomised controlled trial. Setting Paediatric wards or paediatric intensive care units within children’s hospitals ( n  = 4) in the United Kingdom. Participants Children recruited into the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial aged between 72 hours and 18 years old admitted to hospital, and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Recruitment to the sub-study occurred between December 2020 and October 2022. Intervention Procalcitonin-guided algorithm versus usual standard care alone. Main outcome measures Time from starting to stopping intravenous antibiotic therapy was the primary (time-to-event) end point. Baseline mid-regional proadrenomedullin and host immune response biomarkers (tumour necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein 10 and C-reactive protein) defined subgroups for the primary comparison, and serial measurements for additional analyses. Results The primary analysis data set included 305 patients ( n  = 235 in procalcitonin arm; n  = 70 in usual care arm). Median age was 3.7 years, 42.3% (129/305) were female, 94.1% (287/305) were White, and 48.7% (147/302) had at least one comorbidity. Unadjusted p -values suggested potential interaction effects between Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection procalcitonin arm and C-reactive protein on antibiotic duration (intravenous, total, broad-spectrum), indicating a tendency for antibiotic durations to be shorter in the procalcitonin arm than in the usual care arm when baseline C-reactive protein is high, and vice versa when baseline C-reactive protein is low. However, after adjustment for multiple testing none of these effects remained statistically significant at the 5% level. For the other biomarkers at baseline (tumour necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein 10 and mid-regional proadrenomedullin) and outcomes (time to discharge from hospital), there was no interaction. Limitations The study recruited from only four National Health Service sites in England; laboratory analyses were not reproducible and C-reactive protein values did not correlate well with National Health Service laboratory values. Conclusions This research does not support stratification by baseline mid-regional proadrenomedullin and host immune response biomarkers (tumour necrosis factor-related apoptosis-inducing ligand and interferon gamma-induced protein 10) to identify patients who will benefit from a procalcitonin-guided antibiotic algorithm, although stratification by baseline C-reactive protein may identify patients who will benefit from a procalcitonin-guided antibiotic algorithm. Future work Further studies of embedding host immune response stratification within randomised controlled trials in larger numbers of patients are needed. Study registration This study is registered as Current Controlled Trials ISRCTN14945050 (Registered 17 December 2020). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: NIHR129960) and is published in full in Efficacy and Mechanism Evaluation ; Vol. 13, No. 4. See the NIHR Funding and Awards website for further award information.