Erythrocyte Sedimentation Rate and C-Reactive Protein in the ED

Authors: Rachel Kelly, MD (EM Resident Physician, Stony Brook University Hospital) and Robert Nocito, MD (EM Attending Physician, Stony Brook University Hospital) // Reviewed by: Jessica Pelletier, DO (EM Education Fellow, Washington University in St. Louis); Marina Boushra (EM-CCM, Cleveland Clinic Foundation); Brit Long, MD (@long_brit)

Case

A 54-year-old female with a past medical history of rheumatoid arthritis presents to the emergency department (ED) with generalized fatigue. She has had several days of intermittent fevers and chills, body aches, and pain in most of her joints, particularly in her left elbow. In the ED her vitals are T 99.6°F, HR 79 BPM, BP 142/76 mm Hg, RR 15 per minute, and saturation of  99% on room air. Examination reveals a patient with generalized pain, stiffness, swelling throughout most joints and a swollen and tender left elbow. The differential diagnosis includes rheumatoid arthritis flare versus septic arthritis. Would inflammatory markers such as erythrocyte sedimentation rate (ESR) and (CRP) change clinical course or management in the ED?

What Are ESR and CRP?

ESR and CRP are acute-phase reactants with concentrations that change in response to inflammation both acutely and chronically (1). ESR and CRP are widely used in monitoring and detecting multiple inflammatory conditions. ESR measures the rate at which red blood cells settle in a test tube, a factor of the concentration of fibrinogen in the blood, which increases during inflammation (1). ESR is an indirect and imperfect measure of the inflammatory response and can be affected by multiple processes aside from an acute-phase response, including hematologic conditions, obesity, renal failure, heart failure, aging, female sex, pregnancy, and medications (1). CRP is produced by the liver in response to acute infection or inflammation and plays a role in cell death and apoptosis (1). CRP is, therefore, a more direct measure of the inflammatory response but can also be affected by many other processes including age, sex, race, and body mass index (1).

Although ESR and CRP are biomarkers for inflammation, the interpretation of their increase in acute inflammation is different, as patterns of response are different for each test. CRP begins to rise within hours of the start of an infection or inflammatory condition, has a constant half-life of about 18 hours, and will return to normal levels in 3-7 days from the resolution of the underlying process (1,2). Conversely, ESR levels are slower to rise in response to inflammation and infection and will remain elevated for longer as long as excess fibrinogen remains in the serum (1,2). As a result, CRP is a more sensitive marker of the acute inflammatory response, especially within the first few days of a process (1,2).

Clinical Utility

Elevations in ESR and CRP indicate that inflammation is present, but the tests and levels do not specify where. Additionally, elevations in levels, especially a rapid increase in CRP, occur across a wide spectrum of disorders and diseases including infection, trauma, tissue necrosis, malignancies, and autoimmune disorders (1). ESR and CRP are neither sensitive nor specific for any condition and should only be used in conjunction with a good clinical history and physical exam (3). Still, these labs continue to serve as an important adjunct in diagnosing, monitoring, and clinically managing acute and chronic inflammatory conditions (3).

Best practices advise not to routinely order an ESR to evaluate for inflammation in an undifferentiated patient and to instead order a CRP when evaluating for acute inflammation (4). This is because CRP will be elevated in the first few days of an acute inflammatory response, making it more sensitive and specific during this phase compared to ESR, which may be normal at this time (4). After the resolution of a known inflammatory source, ESR can remain elevated and may be useful to trend for days, while CRP will return to normal more quickly (4). These temporal trends in CRP and ESR concentrations can help elucidate the timing and nature of an inflammatory process. For example, a patient with elevated CRP and normal ESR likely has an acute infectious, ischemic, or thromboembolic process present (5). On the other hand, a patient with normal CRP and elevated ESR would likely have a more subacute or chronic autoimmune, systemic inflammatory, or malignant process present (5). This is why in general ESR is more useful for monitoring chronic inflammatory conditions while CRP has increased utility in the monitoring and diagnosis of acute inflammatory conditions (6). Notably, in practice, the combination of ESR and CRP interpretation results in higher diagnostic accuracy and utility. This is why both tests are usually ordered simultaneously, even though their peaks theoretically appear at different times during the acute-phase response and some arguments can be made for their individual use (7,8).

Normal Values

While acute phase reactants such as ESR and CRP are not disease-specific or consistently able to distinguish an acute versus chronic inflammatory process, they have utility in certain ED settings. Normal values for ESR and CRP are listed below, and it is important to note that minimal increases in ESR and CRP are less helpful than multifold increases (5).

Normal values for ESR include (9):

Children: < 10 mm/hr

Males and females < 50 yo: < 15 and 20 mm/hr, respectively

Males and females >50 yo: < 20 and 30 mm/hr, respectively

Normal values for the standard CRP test include (10):

Normal: < 1 mg/dL 

Moderate elevation: 1-10 mg/dL 

Significant elevation: > 10 mg/dL 

Of note, there are two available CRP tests: the standard CRP and the high-sensitivity CRP (hs-CRP) test. Both tests perform the same and do not change the interpretation of CRP values, but the hs-CRP test can detect and report lower levels of elevation compared to the standard test (10).

Emergency Department

As in the inpatient setting, ESR and CRP should only be used as adjuncts to the clinical assessment. They are often more valuable in long-term clinical management than in the acute setting of the ED, and they are unlikely to alter the direct care provided in the ED. While normal ranges exist, cut-off values also vary by diagnosis. There are three main instances where ESR and CRP may be of value to the ED clinician:

A. Back pain – In the ED, some crucial diagnoses regarding back pain include vertebral osteomyelitis, spinal epidural abscess, and malignancy. When ESR or CRP are elevated in the setting of back pain, sensitivity can range from 94% to 100%, and often there are significant elevations in ESR and CRP, even in the absence of leukocytosis (11).

Spinal epidural abscess:

– ESR is more sensitive, but CRP is also usually elevated based on available literature (12)

– Consider this diagnosis and need for further imaging with MRI if ESR > 20 mm/hr and CRP > 1 mg/dL (13)

– ESR can be > 100 mm/hr, and there is a worse prognosis if CRP > 11.5 mg/dL (14,15)

Vertebral osteomyelitis 

– 90% of patients of ESR levels >30 mm/h and CRP >10 mg/L (16)

Malignancy/spinal tumors

– ESR and CRP elevations are typically noted, particularly if disease is systemic (12)

Bottom Line: ESR and CRP elevations can help discern the likelihood of an infectious process that would warrant an MRI, but normal values should not be used to rule out serious diagnoses such as spinal epidural abscess or osteomyelitis in high risk patients (those with neurologic deficit). If used as part of a diagnostic pathway for SEA in a patient with intermediate or low pretest probability, an ESR below the threshold may be used to exclude SEA.

B. Skin and soft tissue infections – In the ED, it is important to determine which patients warrant inpatient admission and when to consider necrotizing soft tissue infections (NSTIs) as a potential diagnosis.

Cellulitis:  

– Average ESR and CRP levels for a more severe disease presentation requiring longer hospitalization are 70 mm/h and 10 mg/dL, respectively (17)

– Average ESR and CRP levels for a less severe disease presentation requiring shorter hospitalization are 50 mm/h and 4 mg/dL, respectively (17)

– Often trended to monitor response to therapy (3)

Necrotizing soft tissue infections (NSTI):

– Clinical scoring tools such as Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score incorporate CRP, but it remains a clinical diagnosis (18)

Bottom Line: On the spectrum of skin and soft tissue infections, ESR and CRP can be helpful in noting disease severity and monitoring treatment and can possibly aid in disposition determination, but these should not change ED management or need for surgical consultation in those with NSTI.

C. Joint and bone pain – In the ED, the primary diagnostic objective in assessing patients with bone and joint pain often includes evaluating for septic arthritis and osteomyelitis.

Septic arthritis:

An ESR > 15 mm/h and CRP > 2 mg/dL are > 90% sensitive for the diagnosis of septic arthritis. However, these elevations are not specific, and lower cutoff values have much lower sensitivity (19).  Definitive diagnosis is made based on synovial fluid analysis (20).

Osteomyelitis: 

In non-diabetic patients, the combination of an ESR >45.5 mm/h and CRP >3.45 mg/dL has a sensitivity of 33% and a specificity of 84% for the diagnosis of osteomyeltis (21).  In diabetic patients, the combination of an ESR > 60 mm/h and CRP > 7.9 mg/dL increase the likelihood of osteomyelitis as a diagnosis (22).

Bottom Line: If concerned for a septic joint, ESR and CRP levels should not change the need for arthrocentesis. ESR and CRP levels cannot rule in or out osteomyelitis; however, higher elevations should increase clinical concern.

Of note, many pediatric and neonatal clinical guidelines incorporate ESR, CRP, and other acute phase reactants in their algorithms, which are not discussed here.  

Pearls and Pitfalls

-ESR and CRP are neither sensitive or specific for infection, and cut-off values for meaningful elevations are based on the disease process in question. Inflammatory markers can be falsely elevated or decreased based on concomitant conditions.

–Do not routinely order ESR and CRP, as elevations are common in a spectrum of diseases, and false positives may be distracting. Results of these tests should not replace clinical judgment. 

-There can be utility when ordering ESR and CRP for back pain in the ED, but normal values should not dissuade the clinician from ordering an MRI if suspicion is high for an infectious process.

-There is some utility in ordering ESR and CRP for skin/soft tissue/bone and joint conditions, although the levels may be more useful for long-term management as opposed to ED clinical decision making.

References

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(4) Choosing Wisely Campaign. American Society for Clinical Pathology recommendations. Available: 

https://www.choosingwisely.org/clinician-lists/american-society-clinical-pathology-erythrocyte-sedimentation-rate-for-acute-phase-inflammation/. Accessed 15 Apr 2023. 

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