Within-Person Variability in High-Sensitivity C-Reactive Protein

To the Editor:

C-reactive protein (CRP) is a marker of systemic inflammation and cardiovascular disease.^1–3 Based on findings from recent clinical trials, CRP has been recommended as an adjunct screening tool to stratify cardiovascular risk in the general population⁴. However, evidence regarding within-person variability of CRP in the general population is limited. Short-term variability in CRP has important implications for its use an interpretation in clinical practice and research studies. Thus, the objective of this study was to evaluate the short-term, within-person variability in CRP measurements and to quantify the impact of repeat testing on CRP-based cardiovascular risk classification.

Methods

Study Population

We included 541 participants aged 16–69 years who completed repeat examinations of the 2001–02 National Health and Nutrition Examination Survey (NHANES). Briefly, a 5% nonrandom sample of 2001–02 NHANES participants were recruited for the second examination, occurring approximately 2.5 weeks after the original examination. Participants represented a uniform distribution of individuals by age, sex, and race/ethnicity. The study design and methods for NHANES are detailed elsewhere.⁵

High-sensitivity serum CRP was measured using latex-enhanced nephelometry⁵. We used a cut-point of ≥1 mg/dL to define elevated CRP, based on the NHANES laboratory reference values and AHA/CDC recommendations.¹ We also conducted sensitivity analyses using a higher cut-point (CRP ≥2 mg/dL).

Statistical Analyses

The Spearman’s and intra-class correlation (ICC) coefficients, and the within-person coefficient of variation (CV_w) were used to characterize short-term within-person variability⁶. Persistently elevated CRP was defined as CRP ≥1 mg/dL at both examinations. We used scatterplots and Bland-Altman plots to visually display measurement variability⁶. Finally, we calculated the percentage of participants whose risk category was reclassified due to repeat testing.

Results

The mean age of participants was 38 years (SD, 16.5). Fifty percent of the study population was female and 48% were of non-Hispanic white race/ethnicity. The mean time between examinations was 18.9 days. Mean CRP was 0.45 mg/dL (95% CI: 0.39–0.51) at the first examination and 0.43 mg/dL (95% CI: 0.38–0.49) at the second examination (p-for-difference=0.45). The Spearman’s correlation between visits was 0.65, the ICC was 0.77 (95% CI: 0.69–0.84), and the CV_w was 46.2% (95% CI: 42.9–49.3%). The high variability in CRP can be seen visually on the scatterplot (Figure 1), although the Bland-Altman plot shows that most of the discordance between examinations occurred at higher values (>1.0 mg/dL) (eFigure 1). The variability was particularly high among persons with CRP >2.0 mg/dL.

Figure 1. Scatterplot of CRP measurements in a subsample of NHANES 2001–2002.

Repeat measurements occurred ~19 days apart. Figure 1A is plotted on the arithmetic scale; Figure 1B is plotted on the natural logarithm scale. Solid lines are placed on the x-axis and y-axis where CRP = 1 mg/dL.

The prevalence of elevated CRP ≥1 mg/dL was 10.5% at the first examination and 10.4% at the second; 7.2% of participants had persistently elevated CRP (eTable 1). Of those with normal CRP at the first examination, only 3.5% had CRP ≥1 mg/dL at the second. Of those with CRP ≥1 mg/dL at the first examination, 32% were reclassified as having CRP <1 mg/dL at the second. The prevalence of CRP ≥2 mg/dL at the first examination was 4.3% and was 2.8% at the second; 1.5% of participants had CRP ≥2 mg/dL at both examinations, representing an approximately 65% decrease in prevalence.

Comment

In this sample of the general population, we observed significant short-term (~2.5 weeks) within-person variability in CRP, particularly at high values. Approximately one third of persons with elevated CRP were reclassified as having normal CRP after repeat testing. Our results are consistent with previous studies conducted in small selected populations (e.g., patients with ischemic heart disease) or where measurements were months or years apart.^7,8 Of note, we observed greater variation at higher values where clinicians are most likely to intervene.

The 2010 American College of Cardiology Foundation/American Heart Association guidelines for the assessment of cardiovascular risk in asymptomatic adults includes recommendations for CRP to select patients for statin therapy when LDL cholesterol concentration is <130 mg/dL.⁹ Our results suggest that use of a single CRP measure for risk stratification may lead to substantial misclassification. Recommendations for repeat testing to confirm elevations in CRP prior to altering medical decision-making may be warranted, particularly among those with CRP values near the risk cut points.