CRP and High-Sensitivity CRP: “What’s in a Name?”

In this issue of JALM, Dr. E. Han and colleagues, from the Medical University of Vienna in Vienna, Austria, report on the results of a well-done retrospective observational cohort study, which was designed to compare the performance of a standard C-reactive protein (CRP) assay (Roche: CRPL3 (1)) and a high-sensitivity CRP (hsCRP) (Roche: CRPHS (2)) assay for cardiovascular risk prediction (3). Both tests are latex particle-enhanced immunoturbidimetric assays and use a mouse monoclonal antibody against CRP. The rationale for the study is that, in general, standard CRP assays are less expensive to perform and are more widely available than hsCRP assays. CRP is produced by hepatocytes and monocytes and plays a crucial role in the inflammatory response to infection and tissue injury, by acting as an acute phase reactant (4). “Fraction C,” its original name, was first reported over 90 years ago by Tillett and Francis (5), who investigated inflammation in patients with pneumonia, bacterial endocarditis, and acute rheumatic fever. In 1950, Anderson and McCarty (6) developed the first semiquantitative test for measuring serum CRP for monitoring rheumatic fever patients. Serum CRP levels can reach levels as high as 500 mg/L during acute infection (7, 8), thus making it relatively easy to detect elevated CRP in infected patients by the first-generation CRP tests. In the late 1990s, however, the important role of chronic low-grade inflammation in the development of atherosclerosis was realized, leading to the use of CRP as a cardiovascular biomarker. For this application, it was necessary to have more sensitive assays (hsCRP tests) to detect values of CRP below 10 mg/L in uninfected individuals. The current US 2018-Multisociety Guidelines on lipids for cardiovascular diseases (CVD) risk assessment (9) state that patients with an intermediate 10-year risk score (7.5% to 20%) and an hsCRP value of ≥2.0 mg/L should be considered to be at an increased risk and may be candidates for lipid-lowering therapy. hsCRP is not recommended to be used as a screening test in the general population. In addition, because of its high biologic variability, it is best to use the mean of 2 or more test results before making any clinical decisions. It can also become acutely elevated in patients with myocardial infarction and many other types of acute illnesses, so it should only be used in stable patients for CVD risk assessment. In the current paper, 570 adults were selected for the study based on their referral for CVD risk assessment in a cardiology outpatient clinic. Anyone with acute infection, active cancer, acute coronary syndrome, or percutaneous coronary intervention within 30 days was excluded. CRP was measured on all the patients by both the standard Roche CRP test (CRPL3 (1)) and the Roche hsCRP test (CRPHS (2)) on a COBAS c 701/702 analyzer (Roche/Hitashi). Overall, the 2 tests yielded similar results, with a highly significant (P < 0.001) positive linear Spearman correlation of 0.988. Bland–Altman analysis showed a small mean difference of only 0.19 mg/L, with an observed trend of the standard CRP skewing towards higher values than the hsCRP test for values above 3 mg/L. The detection limit of the standard CRP and hsCRP assays were 0.3 and 0.15 mg/L, respectively. Next, individuals were classified into the following 3 CVD risk groups based on their serum hsCRP levels: group 1, a low-risk group with hsCRP < 1 mg/L (36.7% of cohort); group 2, an intermediate-risk group with hsCRP 1 to 3 mg/L (39.6% of cohort); and group 3, a high-risk group with hsCRP > 3 mg/L (23.7% of cohort). Using the same cutpoints, the standard CRP assay classified patients similarly into the different risk groups (kappa score = 0.86; SE 0.018). There was total agreement between the 2 tests in identifying the highest risk patients with a hsCRP > 3 mg/L. For 486 patients for which there was a median follow-up period of 28 months, a composite endpoint of acute myocardial infarction, stroke, coronary intervention, or death was determined. Of the patients who developed a cardiovascular event, 16.3%, 15.7%, and 29.1% were from the low-, intermediate-, and high-hsCRP risk groups, respectively. Although this is a relatively small study, it is consistent with many other larger studies showing the value of CRP as a CVD risk biomarker even after adjustment of other risk factors (10). The CVD event outcomes were very similar for the standard CRP test (16.2%, 15.9%, and 27.5% of patients classified as low-, intermediate-, and high-risk groups, respectively). The authors conclude from this study that both the Roche standard test for CRP and the Roche hsCRP test are very comparable in their CVD risk stratification. In William Shakespeare’s play Romeo and Juliet, Juliet poses the question “What’s in a name?,” when trying to convince Romeo to marry her despite his family name of Montague, who were bitter enemies to her family, the Capulets. In the case of CRP tests, the 2 different names, CRP and hsCRP, have important practical implications. In fact, the Food and Drug Administration (FDA) has 3 different designations for CRP tests (11), which affects how these tests are reimbursed, at least in the United States. A standard CRP test is expected to have a minimum starting range of 5 mg/L, whereas an hsCRP test is supposed to have a measuring range starting below 1.0 mg/L and extending to at least 10 mg/L. An hsCRP test that has also been demonstrated to be useful for CVD risk assessment from either a clinical study or by showing that it is analytically equivalent to a predicate hsCRP test already established to have clinical utility as a CVD risk biomarker, is designated as a cardiac CRP (cCRP) test. The cCRP designation, however, is mostly only used by the FDA. The 2022 Clinical Diagnostic Laboratory Fee Schedule of the American Medical Association lists the regular CRP test reimbursement price of $5.18 vs $12.95 for hsCRP testing when its intended use is for CVD risk assessment as described by the US 2018-Multisociety Guidelines (9). Because of the regulatory rules in the United States, the use of a standard CRP test for cardiovascular risk assessment may pose problems if a clinical laboratory tries to get reimbursed by either public or private insurers at the same rate as a hsCRP test. Once a diagnostic company applies for and is granted cCRP status from the FDA, the use of a test that was once considered a standard CRP assay for CVD risk assessment should not be a problem. Alternatively, a clinical laboratory could potentially perform all the validation studies and complete the documentation to enable it to use a standard CRP test for CVD risk assessment as a “Laboratory Developed Test,” but few clinical laboratories would likely have the resources for doing this. So to answer Juliet’s question, for at least CRP tests, a name means quite a lot. It is a challenge because technology is always evolving, but it is important to always try to align the true costs of clinical laboratory testing with reimbursement rates, because otherwise it may create disincentives for doing what might be best for patients. Another related example of this issue is apolipoprotein B (apoB), which has been shown to be superior to other lipid tests as a CVD biomarker (12), but because of its high apparent costs compared to the standard lipid panel, it is often underutilized. As with the case of the standard CRP and hsCRP assays described here, there has been a great consolidation in the types of analyzers used by clinical laboratories. In particular, the vast majority of clinical chemistry tests, including apoB and the lipid panel tests, are now all done on the same analyzer. It is also important to note that the cost of developing a test and the cost of manufacturing the different reagents that go into various diagnostic tests are often not that different, despite sometimes large differences in their reimbursement rate. In summary, this paper nicely shows that because of improvements in standard CRP testing, some of these tests may now be sufficiently sensitive for CVD risk assessment. But in order to fully realize this opportunity and the other future advances in laboratory testing, it is important that we regularly update reimbursement rates to better align with real costs as technology changes, in order to make sound economic judgments on the value of different diagnostic testing approaches. Nonstandard Abbreviations: CRP, C-reactive protein; hsCRP, high-sensitivity C-reactive protein; CVD, Cardiovascular Diseases. Author Contributions:All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: Research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health. Expert Testimony: None declared. Patents: None declared.