Within-subject variation of C-reactive protein and high-sensitivity C-reactive protein: A systematic review and meta-analysis

Background: C-reactive protein (CRP) and high-sensitivity C-reactive protein (hsCRP) are measures of inflammation used in diagnosis, to guide treatment decisions, and in disease prediction. Variability in measured CRP and hsCRP may affect their clinical utility but estimates of within-subject variability are based on limited data. Methods: A systematic review and meta-analysis was performed to estimate longitudinal within-subject variability of CRP and hsCRP over any time period. Follow-up studies of any design in adults or children, with repeated measures of CRP or hsCRP were sought. Multiple databases were searched from inception to November 2022. Titles and abstracts were screened in duplicate. Full text screening and data extraction were performed by one reviewer and verified by a second. Risk of bias was assessed with a modified Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) tool. Intraclass correlation coefficient (ICC) results were pooled with a meta-analysis and coefficient of variation (CV) results were described by median and range. Results: Of 2675 studies identified, 60 met the inclusion criteria: 34 reported CRP and 26 reported hsCRP. For CRP, median CV was 0.41 (range 0.11 to 0.89), and the pooled estimate of ICC was 0.55 (95% CI 0.35 to 0.74). For hsCRP, median CV was 0.44 (range 0.27 to 0.76) and the pooled estimate of ICC was 0.62 (95% CI 0.58 to 0.67). Limitations: Assessment of variability was not the main aim of many of the included papers, and it is possible that some relevant papers have been missed. Many of the papers included had low numbers of participants and/or low numbers of repeated measurements. Conclusions: Estimated within-subject variability is high for both CRP and hsCRP, but estimates are based on small numbers of participants and measurements. There is a need for better estimates of within-subject variability from analysis of larger numbers of repeated measurements in larger numbers of subjects.