Optimum cutoff values for absolute neutrophil count and C-reactive protein in the management of febrile infants at risk of invasive bacterial infection. A prospective multicentre study across the UK

Background
Febrile infants are at risk of invasive bacterial infection (IBI) necessitating prompt treatment. This can lead to an overly cautious approach for the management of these infants. In recent years, sequential assessment has been implemented in North America and Europe, incorporating biomarkers, such as absolute neutrophil count (ANC) and C-reactive protein (CRP). Multiple cutoffs for both biomarkers have been proposed in the literature with no current evidence from a UK population. This study aimed to evaluate the proposed cutoffs for ANC and CRP in the sequential assessment of febrile infants at risk of IBI.
Methods
The febrile infant diagnostic assessment and outcome (FIDO) study is a multicentre prospective observational study of febrile infants (0–90 days) presenting to the emergency department. Patients were recruited from centres across the UK from July 2022 to August 2023. The patients underwent routine care at each centre. IBI was defined as a single growth of bacterial organism in the blood or cerebrospinal fluid. ANC cutoffs assessed were 4.0, 5.2 and 10 x 109/l. CRP cutoffs were 13.1, 15, 16.2 and 20 mg/l. The diagnostic performance was reported for each cut off and the rate of IBI in low risk cohort.
Findings
The first 1000 patients from 25 centres were used for this interim analysis. The median age was 44 days (IQR: 27 – 62 days), with a male predominance of 60%. Of the 1000 infants, 4.2% (n-45) had IBI. Blood tests were done in 91% of infants with 879 infants having results for ANC (41 with IBI) and 913 for CRP (45 with IBI). The sensitivity and specificity of ANC 4.0, 5.2, and 10 x 109/l were 0.68/52, 0.51/0.67, and 0.22/0.91, respectively. For CRP cutoffs 13.1, 15, 16.2 and 20 mg/l, the sensitivity/specificity were 0.76/0.58, 0.76/0.60, 0.76/0.63 and 0.71/0.68 respectively. The cutoff with the lowest rate of IBI in a low risk population for ANC was 4.0 X109/l (2.9% -13/449), while for CRP it was 16.2 mg/l (1.9%-11/556). The AUC for ANC and CRP were 0.65 (CI: 056 – 0.74) and 0.77 (CI: 0.70 – 0.84) respectively.
Interpretation
The optimum cutoff values for ANC and CRP were 4.0 X109/l and 16.2 mg/l respectively, within a large UK cohort. Lower thresholds could be applied in the sequential evaluation of febrile infants to improve their care and effectively identify a low-risk group that can be managed without invasive tests or the need for hospitalization. Future studies will need to validate clinical decision aids incorporating these cutoffs, particularly in the context of a UK population