Longitudinal hsCRP assessment in routine care refines residual inflammatory risk estimates

Introduction Elevated levels of high-sensitivity C-reactive protein (hsCRP) identify patients with a high inflammatory risk eligible for anti-inflammatory therapies. In routine care, hsCRP fluctuates due to comorbidities and concomitant medications, potentially leading to risk misclassification when based on a single measurement. Guideline recommendations only partially address testing strategies and variability of hsCRP outside controlled clinical trials. Methods This retrospective, observational study used routinely collected data from two sites at a German university hospital (Q1 2010–Q2 2024) for a secondary analysis in patients with a high prevalence of cardiovascular disease. The dataset included hsCRP measurements, diagnoses coded with ICD-10, and procedure records based on the German OPS classification. Intra-individual variability was evaluated in patients with at least two measurements using patient-level coefficients of variation (CV). Repeated testing was examined in patients with 5 or more measurements, with a median time between measurements of 234 days. In our analysis strategy, we defined that the lowest hsCRP value observed across all measurements served as an estimate of the true individual inflammatory baseline. An hsCRP >2 mg/L was classified as an elevated inflammatory risk. Misclassification at one time point was defined as hsCRP >2 mg/L when the true baseline was <2 mg/L. Results Our analysis comprised 9,110 unique patients with 15,197 hsCRP measurements (mean 2.07 mg/L; median 1.30 mg/L; SD 1.96; population-level coefficient of variation (CV) 0.95). Among 2,585 patients with ≥2 measurements (n=9,060), mean hsCRP was 1.87 mg/L (median 1.20 mg/L) with substantial intra-individual variability (SD 1.83; mean patient-level CV 0.48). Median age was 71 years, and 70% were male. The first of 5 consecutive measurements indicated a residual inflammatory risk in 34.3% of individuals. A reallocation to lower-risk categories due to hsCRP < 2 mg/L in the second measurement occurred in 16.1% of all individuals; thus, 18.2% persisted in the hsCRP >2 mg/L risk category. Serial testing progressively shifted patients into lower strata: the ≤1 mg/L category increased from 43% at the first measurement to 76.2% after the fifth measurement. Consequently, the fraction of individuals with a persistently high inflammatory burden (hsCRP >2 mg/L) fell to 7.9% after 5 measurements. Importantly, the lowest hsCRP value was observed uniformly across all measurement positions, without a consistent temporal pattern. Conclusion A single measurement of hsCRP misclassifies a substantial proportion of patients into higher risk categories. Serial testing reduces upward classification and false positives driven by transient elevations. When applied, the fraction of individuals with a high inflammatory burden is considerably lower than previously reported. Thus, inflammatory risk is a common feature but less frequent than expected.