General Inflammation Testing - CAM 205HB
Description
Inflammatory response can occur due to tissue injury and/or various disorders, including arthritis, lupus, and infection. Acute phase reactants, such as serum C-reactive protein (CRP), are released in the acute phase response during inflammation and can be used to monitor inflammation. Inflammation may also be measured using the simple laboratory technique of erythrocyte sedimentation rate (ESR) (Kushner, 2024).
For guidance on the use of CRP as a cardiac biomarker, please see policy CAM 193-Biomarkers for Myocardial Infarction and Chronic Heart Failure. For guidance on the use of CRP as a marker for acute pancreatitis, please see CAM 198-Pancreatic Enzyme Testing for Acute Pancreatitis.
Regulatory Status
Testing of serum acute phase reactants and ESR is performed in laboratories meeting Clinical Laboratory Improvement Act (CLIA) quality standards. The FDA has approved multiple tests for human CRP, including assays for conventional CRP, high sensitivity CRP (hsCRP), and cardiac CRP (cCRP). On Sept. 22, 2005, the FDA issued guidelines concerning the assessment of CRP (FDA, 2005). A search of the FDA Medical Devices database (FDA, 2018) on June 12, 2018, shows that the FDA has approved ESR systems from multiple companies, including the ESR Control -M Hematology Erythrocyte Sedimentation system (K972172) and the ESR Control -HC Hematology Erythrocyte Sedimentation system (K972170) by R & D Systems, the Seditainer Erythrocyte Sedimentation Rate System (K953994) from Becton Dickinson Vacutainer Systems, the Westergren Dispette for ESR (K831195) by Ulster Scientific, and the Dade ESR Kit (K823368) from American Dade.
Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.
- Measurement of C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) is considered MEDICALLY NECESSARY for inflammatory conditions as specified in Note 1.
- For individuals without a diagnosed inflammatory condition, measurement of ESR is considered NOT MEDICALLY NECESSARY.
- Measurement of CRP and/or ESR during general exam without abnormal findings is considered NOT MEDICALLY NECESSARY.
NOTES:
Note 1: Coverage of CRP, ESR, CRP or ESR, or both CRP and ESR is designated based on the diagnosed or suspected inflammatory condition. Either conventional or high-sensitivity CRP testing are allowed methods of testing for CRP levels. When either CRP or ESR are allowed, CRP is the preferred biomarker.
| Condition |
Test Preference |
Frequency of Testing |
| Acute and Chronic Urticaria |
CRP or ESR |
Not specified (NS) |
| Acute Hematogenous Osteomyelitis (AHO) |
CRP |
To confirm diagnosis; 2 to 3 days during the early therapeutic course; weekly until normalization (or a clear trend toward normalization is evident) |
| Acute Phase Inflammation |
CRP |
NS |
| Ankylosing Spondylitis |
CRP or ESR |
Regular interval use in patients with active symptoms |
| Arthritis |
CRP and ESR |
1 – 3 months initially; 6 – 12 months later |
| Castleman’s Disease |
CRP |
NS |
| General Inflammation |
CRP |
NS |
| Hodgkin Lymphoma |
ESR |
Every 3 to 6 months for 1 to 2 years; every 6 to 12 months for the next 3 years; annually thereafter |
| Irritable Bowel Syndrome |
CRP and ESR |
During initial assessment to exclude other diagnoses |
| Large Vessel Vasculitis (Giant Cell Arteritis, Takayasu Arteritis) |
CRP and ESR |
To confirm diagnosis; every 1 – 3 months during the first year; every 3 – 6 months thereafter |
| Nonradiographic axial spondyloarthritis |
CRP or ESR |
Regular interval use in patients with active symptoms |
| Polymyalgia Rheumatica |
CRP or ESR |
At initial diagnosis; every 3 months during long-term steroid therapy |
| Periprosthetic Joint Infections (PJI) |
CRP and ESR |
NS |
| Rheumatoid Arthritis |
CRP or ESR |
Prior to treatment; every 1 – 3 months during active disease; annually when disease is inactive |
| Systemic Lupus Erythematosus |
CRP or ESR |
At initial assessment; every 1 – 3 months during active disease; every 6 – 12 months during stable disease; during pregnancy |
| T-cell lymphomas |
ESR |
NS |
TABLE OF TERMINOLOGY
| Term |
Definition |
| AAAAI |
Academy of Allergy, Asthma & Immunology |
| AAFP |
American Academy of Family Physicians |
| AAOS |
American Association of Orthopaedic Surgeons |
| AAOS |
American Academy of Orthopaedic Surgeons |
| ABIM |
American Board of Internal Medicine |
| ABVD |
Adriamycin, bleomycin, vinblastine, dacarbazine |
| ACAAI |
American College of Allergy, Asthma & Immunology |
| aCL |
Anticardiolipin |
| ACPA |
Anti-cyclic citrullinated peptide antibodies |
| ACR |
American College of Rheumatology |
| ACR |
American College of Radiology |
| ANA |
Antinuclear antibodies |
| Anti-CCP |
Anti-cyclic citrullinated peptides |
| Anti-dsDNA |
Anti-double stranded DNA |
| Anti-β2-GPI |
Anti-β2-glycoprotein I |
| aPL |
Antiphospholipid antibodies |
| AS |
Ankylosing spondylitis |
| ASCP |
American Society for Clinical Pathology |
| ASCP |
Anti-cyclic citrullinated peptide antibodies |
| AUC |
Area under the curve |
| BHPR |
British Health Professionals in Rheumatology |
| BSR |
British Society for Rheumatology |
| CBC |
Complete blood count |
| cCRP |
Cardiac C-reactive protein |
| CDAI |
Clinical disease activity index |
| CHL |
Classic Hodgkin lymphoma |
| CLIA |
Clinical laboratory improvement act |
| CRA |
Canadian Rheumatology Association |
| CRP |
C-reactive protein |
| CTD |
Connective tissue diseases |
| CVD |
Cardiovascular disease |
| DAS |
Disease activity score |
| DAS28 |
28-Joint disease activity score |
| DAS28-CRP |
Disease activity score 28 C‐reactive protein |
| DAS28-ESR |
Disease activity score with 28-joint counts - erythrocyte sedimentation rate |
| EDL |
Essential In Vitro Diagnostics |
| EDTA |
Ethylenediamine tetraacetic acid |
| eGFR |
Estimated glomerular filtration rate |
| EIA |
Enzyme immunoassay |
| ENA |
Extractable nuclear antigens |
| ESR |
Erythrocyte sedimentation rate |
| EULAR |
European League Against Rheumatism |
| FDA |
Food and Drug Administration |
| GCA |
Giant cell arteritis |
| HCSC |
Health care service corporation |
| HL |
Hodgkin lymphoma |
| hsCRP |
High-sensitivity C-reactive protein |
| IBD |
Inflammatory bowel disease |
| IBS |
Irritable bowel syndrome |
| ICSH |
International Council for Standardization in Hematology |
| ISRT |
Involved-site radiation therapy |
| IVD |
In vitro diagnostics |
| JTFPP |
Joint Task Force on Practice Parameters |
| LAC |
Lupus anticoagulant |
| LDH |
Lactate dehydrogenase |
| MCD |
Multicentric Castleman Disease |
| MSIS |
Musculoskeletal Infection Society |
| NA |
Not applicable |
| NASH |
Nonalcoholic steatohepatitis |
| NCCN |
National Comprehensive Cancer Network |
| NICE |
National Institute for Health and Care Excellence |
| NPV |
Negative predictive value |
| NS |
Not specified |
| NSAID |
Non-steroidal anti-inflammatory drugs |
| PAS |
Patient activity scale |
| PJI |
Periprosthetic joint infections |
| PMR |
Polymyalgia rheumatica |
| PPV |
Positive predictive value |
| RA |
Rheumatoid arthritis |
| RACGP |
Rheumatoid Arthritis Working Group of The Royal Australian College of General Practitioners |
| RAPID3 |
Routine assessment of patient index data 3 |
| RD |
Rheumatic disease |
| RDT |
Rapid diagnostic test |
| RF |
Rheumatoid factor |
| SAA |
Spondylitis Association of America |
| SDAI |
Simplified disease activity index |
| SIRS |
Systemic inflammatory response syndrome |
| SLE |
Systemic lupus erythematosus |
| TSH |
Thyroid-stimulating hormone |
| VASDA |
Visual analog scale disease activity |
| VASQOL |
VAS quality of life |
| WHO |
World Health Organization |
Rationale
Conditions Associated with Acute Inflammatory Responses
Diseases most associated with an acute inflammatory response measured by C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) include arthritis, especially rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), giant cell arteritis (GCA), systemic lupus erythematosus (SLE), cardiovascular disease (CVD) (Kushner, 2024), and Hodgkin lymphoma (HL) (NCCN, 2024b). RA is a systemic polyarthritis that can lead to joint loss as well as tendon and ligament deformation to the point of affecting day-to-day living. The diagnosis of RA can be made in a patient “with inflammatory arthritis involving three or more joints, positive RF [rheumatoid factor] and/or anti-citrullinated peptide/protein antibody, disease duration of more than six weeks, and elevated CRP or ESR, but without evidence of diseases with similar clinical features” (Baker, 2024). PMR “is an inflammatory rheumatic condition characterized clinically by aching and morning stiffness about the shoulders, hip girdle, and neck” (Salvarani & Muratore, 2023a). PMR is frequently associated with GCA (also known as Horton disease), which is vasculitis of medium-to-large blood vessels and can include the aorta and cranial arteries. Cranial arteritis can lead to permanent vision loss. An estimated 40% – 50% of patients with GCA also suffer from PMR whereas 15% of all PMR patients are also diagnosed with GCA. Due to inflammation of the aorta and aortic branches, aortic aneurysm and aortic dissection can occur in patients with GCA (Salvarani & Muratore, 2023b). In both PMR and GCA, ESR and CRP levels are typically elevated. SLE “is a complex autoimmune disease with chronic relapsing-remitting course and variable manifestations leading a spectrum from mild mucocutaneous to devastating, life-threatening illness… Epigenetic modifications mediate the effect of the environment on immunologic responses, eventually leading to an inflammatory, autoimmune, multi-systemic disease characterized by autoantibody production and tissue injury” (Gergianaki & Bertsias, 2018). Since patients with SLE can be prone to infection, ESR and CRP may be used in monitoring inflammation (Kushner, 2024). CVD is a very common inflammatory disorder in the United States. Although serum CRP is a non-specific inflammatory marker and is not a causative agent of CVD, serum CRP can be used as a biomarker for CVD (Black et al., 2004; Kushner, 2024). Hodgkin lymphoma accounts for 10% of lymphomas and is characterized as a B-cell lymphoma “containing a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background” (Aster & Pozdnyakova, 2022). ESR is elevated in HL, and an ESR ≥50 is considered as an “early-stage unfavorable factor” (NCCN, 2024b).
Erythrocyte Sedimentation Rate (ESR)
Erythrocyte sedimentation rate (ESR) is a common laboratory method used to monitor general inflammation. ESR is used to analyze many different conditions, including RA, SLE, arteritis, PMR (Kushner, 2024; Wu et al., 2010). The simple Westergren method of ESR consists of measuring the distance a blood sample travels in a tube within one hour. The International Council for Standardization in Hematology (ICSH) established a calibration reference to this method using citrate-diluted samples. Automated ESR methods have been established; however, some of these analyzers use different dilution solutions, such as EDTA, rather than citrate. EDTA is commonly used as an anticoagulant in hematology measurements whereas the use of citrate is less prevalent. Horsti et al. (2010) compared blood samples from 200 patients using the traditional Westergren method versus an EDTA-based method. Their data has an R2 value of only 0.72 and 55 subjects had a difference of over 30%, clearly indicating that ESR is significantly affected by sample preparation methods (Horsti et al., 2010). ESR can also be affected by red blood cell morphology, ambient conditions (such as high room temperature or tilting of the ESR tube), anemia, renal disease, obesity, heart failure, and hypofibrinogenemia (Kushner, 2024; Taylor & Deleuran, 2024).
More, ESR may be affected by noninflammatory factors, thus reducing its specificity for inflammatory processes. Noninflammatory biological factors and environmental conditions can increase a sample’s observed ESR. If the serum sample contains elevated concentrations of ions or charged proteins, an elevated ESR may occur; for example, an increase in positively charged plasma proteins could result in agglutination of erythrocytes within a sample for rapid sedimentation (Hale et al., 2019).
The ICSH established a Working Group to investigate the ESR methodology used in laboratories; the findings of this working group were published in 2017. Data from over 6000 laboratories on four different continents was examined. Of the laboratories included in the study, only 28% used the “gold standard” Westergren method exclusively (i.e. the method with the established validation by the ICSH) “while 72% of sites used modified or alternate methods.” The data obtained from the new methodologies could deviate from the Westergren method by up to 142% and could differ “from each other of up to 42%.” The ICSH released recommendations based up the results of these studies. One such recommendation for labs using the non-Westergren method of ESR is to “consider adding an interpretative comment to every result stating that ‘This result was obtained with an ESR instrument that is not based on the standard Westergren method. The sensitivity and specificity of this method for various disease states may be different from the standard Westergren method’” (Kratz et al., 2017).
Besides the Westergren method, other methods have been developed to measure ESR including the Zeta sedimentation ratio, Wintrobe’s method, and micro-ESR. In a validation study, Shaikh discussed the use of the Ves-Matic Cube 30 analyzer to address the drawbacks of the Westergren method such as contamination risk, the significant blood volume required, and increased duration of analysis. A strong positive correlation was observed between Westergren and Ves-Matic methods with Spearman’s coefficient of 0.97. The study concluded that Ves-Matic Cube 30 analyzer can be used in high workload clinical settings for ESR measurement as the generated results were in concordance with those from the Westergren method.
C-reactive Protein (CRP)
C-reactive protein (CRP) was first discovered in the early twentieth century when it was isolated in a co-precipitation reaction with the pneumococcal C polysaccharide. The polysaccharide component bound by CRP later was identified to be phosphocholine. Since then, studies have shown that CRP can bind ligands other than bacterial cell wall components. During an acute inflammatory response, hepatocytes can upregulate CRP synthesis more than 1,000-fold. The increase in serum CRP “after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response” (Black et al., 2004). Determining CRP concentration and fluctuations in plasma CRP can be useful in monitoring inflammatory response; however, what dictates “normal” CRP levels is of debate since CRP concentrations can vary considerably between individuals, people groups, and laboratory testing methodology. The units used to denote CRP concentrations also vary between laboratories (Kushner, 2024).