Defining normal inflammatory marker and vital sign responses to suspected bloodstream infection in adults with positive and negative blood cultures
Authors: Gu Qingze , Wei Jia , Yoon Chang Ho , Yuan Kevin , Jones Nicola , Brent Andrew , Llewelyn Martin , Peto Tim EA , Pouwels Koen B , Eyre David W , Walker A Sarah 
Published: October 2023

AbstractBackgroundPatients respond differently to bloodstream infection (BSI) and associated antibiotic treatment, for many reasons, including different causative pathogens, sources of infection, and patient characteristics. This heterogeneity can hamper use of different clinical parameters to track treatment response as the same absolute values, or even change from presentation, may have different implications, depending on the expected trajectory, which is often incompletely understood.MethodsWe included patients ≥16y from Oxford University Hospitals (01-January-2016 to 28-June-2021) with any blood culture taken, grouping cultures into suspected BSI episodes (14-day de-duplication). We used linear and latent class mixed models to estimate trajectories in C-reactive protein (CRP), white blood count, heart rate, respiratory rate and temperature and identify subgroups with heterogenous CRP responses. Centile charts for expected CRP responses were constructed via the lambda-mu-sigma method.Findings88,348 suspected BSI episodes occurred in 60,647 adults; 6,910(7.8%) were culture-positive with a probable pathogen (1,914[2.2%] Gram-positive, 3,736[4.2%] Gram-negative, 1,260[1.4%] other pathogens/polymicrobial), 4,307(4.9%) contained potential contaminants, and 77,131(87.3%) were culture-negative. Overall, CRP levels generally peaked between day 1-2 after blood culture collection, with varying responses for different pathogens and infection sources in adjusted models (interaction p<0.0001).We identified five different CRP trajectory subgroups: peak on day 1 (36,091;46.3%) or 2 (4,529;5.8%), slow recovery (10,666;13.7%), peak on day 6 (743;1.0%), and low response (25,928;33.3%). 42,818(63.5%) culture-negative vs. 5,879(89.6%) pathogen-culture-positive episodes had acute response (day 1-2 peak/slow recovery). Centile reference charts constructed from those peaking on day 1-2 showed the same post-presentation CRP values and change from presentation reflected different responses depending on patients’ initial values.InterpretationAlthough infection sources and pathogens are associated with varying responses to BSI, there is distinct underlying heterogeneity in responses. The centile reference charts developed could facilitate more precise tracking of recovery, enable identification of patients not recovering as expected, and help personalise infection management.Research in contextEvidence before this studyWe searched PubMed up to 28 June 2023, for published English articles with the terms “response” AND (“pattern” OR “trend” OR “trajector*”) AND (“bloodstream infection” OR “sepsis”). No studies described pathogen-specific response trajectories for laboratory tests and vital signs. Several studies identified sepsis sub-phenotypes using group-based trajectory modelling based on trajectories of vital signs, white blood cell and Sequential Organ Failure Assessment score. Specifically, three studies identified four temperature trajectory subgroups using measurement within first 72h: “hyperthermic, slow resolvers”, “hyperthermic, fast resolvers”, “normothermic”, and “hypothermic”. One study identified seven different systolic blood pressure trajectory subgroups using measurements within 10h after hospitalisation and investigated their association with hospital mortality. One study identified seven white blood cell (WBC) count trajectories over the first seven days in the ICU and concluded rising trajectory was independently associated with increased mortality compared with the stable trajectory. Another study found four sub-phenotypes based on four different longitudinal vital signs from the first 8h of hospitalisation, including temperature, heart rate, respiratory rate, systolic and diastolic blood pressure. Several studies used Sequential Organ Failure Assessment score to identify trajectory subgroups, and they identified four or five subgroups using data from the first 72h or first 8 days. There were no published studies estimating expected C-reactive protein (CRP) response in standard responders.Added value of this studyTo our knowledge, this is the first study to characterise pathogen-specific and infection source-specific response trajectories of multiple clinical parameters, including CRP, WBC count, heart rate, respiratory rate, and temperature. We identified five different CRP trajectory subgroups and found that 42,818 (63.5%) of culture-negative vs. 5,879 (89.6%) of pathogen-culture-positive episodes had acute response, i.e. a peak in CRP on day 1 or 2 or a slow recovery, and that these CRP subgroups had equivalent parallel responses for the other clinical parameters. Centile reference charts (analogous to paediatric growth charts) were created based on the standard CRP responders (i.e., a peak in CRP on day 1 or 2, assuming that these reflected “normal” response to effective antibiotics). These can be used to standardise assessment of infection progression and treatment response in patients with suspected bloodstream infection given the heterogeneity in these responses. These reference charts could be useful to guide management independent of microbiological test results, e.g., prior to culture results becoming available.Implications of all the available evidencePatient characteristics and host responses are heterogeneous, both initially at presentation and throughout responses to infection, making it challenging to define a single “normal” response to culture-positive and culture-negative suspected bloodstream infection. By applying centile-based methods to large-scale electronic health records, we provide a visually intuitive means of assessing biomarker response, potentially aiding clinical decisions by allowing individual-level observations to be assessed against evidence-based references for expected recovery in patients treated with effective antibiotics, taking into account individual-level heterogeneity.