Diagnostics: Inflammatory Markers

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As the name would suggest, inflammatory markers are biological markers of, well, inflammation.  They are used clinically to detect pathological inflammation or measure response to treatment [1-2]. Colloquially, “inflammatory markers” typically refer to laboratory tests that measure specific acute phase proteins (also known as “acute phase reactants”) [1-5]; however, this term is vaguely defined and can encompass any so-called “marker of inflammation,” including the test we commonly describe to patients as exactly that, the white blood cell count (WBC) [6-7]. It is appropriate, then, that such a vague term is associated with equally vague utility in the clinician’s armamentarium. In this post, we will try to briefly elucidate in the inflammatory response, identify inflammatory markers of clinical significance, and discuss the evidence guiding the use of these markers for the emergency clinician.

The Inflammatory Response

Inflammation is the immune system’s response to harmful stimuli, such as tissue injury or microbial infection [1,8-9]. It triggers a variety of local and systemic processes that attempt to remove the harmful stimuli and initiate repair of the damage, thereby seeking a return to homeostasis. These processes include physiologic changes that amplify the body’s defenses (i.e. fever, complement activation/opsonization, leukocyte recruitment) and augment tissue healing (i.e. hemostasis/coagulation, increased vascular permeability, fibrinogen production). Many of these changes are mediated through the acute phase response [1,3,8-11].

The Acute Phase Response (APR)

The APR is the body’s immediate innate, non-specific systemic reaction to a disturbance in homeostasis. It is initiated by a local insult, such as infection or tissue injury; this leads to the production of pro-inflammatory cytokines with very short half-lives, such as interleukin-1, interleukin-6 (IL-6), interferon-γ (IFN-γ), and tumor necrosis factor alpha (TNF-α). This local inflammatory response is amplified and results in a systemic response including fever, vasodilation, leukocytosis, pro-coagulatory changes, and alterations in production of acute phase proteins (APPs), which are proteins whose concentration increases or decreases by >25% during inflammatory processes [1,3,8-11]. 

IL-6 is considered to be the chief regulator of the APPs by modulating their production in hepatocytes. Production of these proteins is altered within a few hours of the APR, but the rate of change and timeline of this change is variable [12-13]. Furthermore, the same changes in APP production may accompany multiple disease states, so they are very non-specific and indicate the presence of inflammation, in general [2-5,12].

The “acute” part in APR refers to the fact it is the body’s earliest response to infection or injury, but it does not guarantee the response will be short-lived. Ideally, a stimulus activates the APR which in turn produces APPs that lead to removal of the inciting stimulus and shortly thereafter the APR ends with subsequent downregulation and removal of the APPs. Typically, APPs reach a peak within 24 to 48 hours after initiation and start to resolve within 4 to 7 days due to negative regulation if there is no repeated stimulus [12,14]. However, in many pathologies the inflammatory stimuli cannot be completely removed, resulting in repeated activation of the APR and subsequent dysregulation of immune processes that can sustain an APR indefinitely [1,8,12-14]. 

Circling back to the namesake of this article, when someone references “inflammatory markers” in a clinical setting, they are probably referring to two laboratory assays that measure APPs: C-reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR) [1-5]. A third APP, procalcitonin (PCT), is much newer but is often frequently discussed in the same circle as CRP and ESR.

+ C-Reactive Peptide (CRP)

Etiology: Named after the C-polysaccharide of Streptococcus Pneumoniae, CRP was discovered in the serum of patients infected with S. Pneumoniae in 1930 [15]

Function of the biomarker: CRP acts as part of the innate immune system by binding to phosphorylcholine on microbes, such as S. Pneumoniae, thereby opsonizing pathogens for complement binding or macrophage phagocytosis. It also aids in the clearance of necrotic and apoptotic cells. [3,12-14,16-17]

Kinetics & Reference Ranges: In healthy people, CRP levels are normally <10mg data-preserve-html-node="true"/L, in chronic metabolic inflammation (i.e. diabetes mellitus, heart disease), levels are between 2-10mg/L [8,12]. In the setting of acute inflammation, the APR is activated and the liver produces CRP. The CRP level rises by 4-6 hours, doubles every 8 hours, and peaks around 48 hours at 100 to 1,000 fold. Its half-life is 19 hours and it is cleared from the plasma at that rate once the stimulus is removed, regardless of kidney function [19]. CRP is a good measure of the overall degree of inflammation because the serum concentration reflects the intensity of the stimulus [3-4,12-14,16-20].

CRP is more elevated in bacterial infections compared to viral infections. This is because bacterial infections produce specific cytokines (TNF-α and IL-1β) that lead to more robust production of IL-6 and therefore a more robust APR in hepatocytes. Viral infections produce IFN-γ which induces hepatocytes to a lesser extent. The exception is viral infections that cause cell lysis, which leads to a comparable APR [12-13].

  • In viral infections, CRP is usually 10-40mg/L;
  • In mild bacterial infections (i.e. cellulitis) or moderately inflammatory stimuli, it is usually 50-100mg/L;
  • In severe bacterial infections, it is >100-200mg/L [20-21].

+ Erythrocyte Sedimentation Rate (ESR)

Etiology: ESR measures the distance erythrocytes fall in a vertical vial of anticoagulated blood; traditionally the test was measured over an hour, but new methods involving centrifugation can complete it in 5 minutes. It was first discussed in the 1890’s by a Polish physician studying rheumatic fever who discovered elevated fibrinogen levels lead to increased ESR. However, the test did not receive attention until the 1920s, at which time it was standardized by Dr. Westergren using sodium citrate as the anticoagulant (which is why it is sometimes referred to as Westergren’s Sedimentation Rate) [3-5,21-22].

  • Notably, ESR is a very old, very simple, and very cheap test, which makes it useful worldwide due to its accessibility [21-22].

Function of the biomarker: N/A

Kinetics & Reference Ranges: ESR is an indirect test of inflammation that is primarily elevated by erythrocyte rouleaux formation, which is regulated by the amount of fibrinogen present. However, the test can be significantly altered by other factors such as RBC size/shape and presence of other proteins, like immunoglobulins. ESR rises slowly and is not significantly increased until 24-48 hours after onset of inflammation, with a correspondingly slow fall over days-to-weeks [3-5, 21-22]. These slow kinetics are primarily due to the kinetics of fibrinogen, which is synthesized by the liver and has a half-life of 3-4 days [23].

  • Normal reference ranges vary by age and gender. The standard reference unit is mm / hr, which measures the distance erythrocytes fall in an hour
  • For age < 50: men 0-15 mm/hr, women 0-20 mm/hr.
  • For age > 50: men 0-20 mm/hr, women 0-30 mm/hr [22]

In general, ESR is becoming less popular due to increasing availability and decreasing cost of more direct assays for inflammation, such as CRP. With that said, ESR > 100 mm/hr is still considered a strong indicator of an active pathological inflammatory process [2-5,21-22].

+ Procalcitonin (PCT)

Etiology: PCT was first discovered in 1984. However, it was not until a 1993 study that its significance was realized. In a small study involving 79 hospitalized children, PCT was found to be elevated in bacterial infections, with a decrease after appropriate antibiotic therapy, and decreased in viral infections [24].

Function of the biomarker: Under normal conditions, pre-procalcitonin is produced by thyroid parafollicular C cells, subsequently cleaved by peptidases into procalcitonin, and finally enzymatically converted into calcitonin, which serves as a negative regulator of calcium homeostasis. As a prohormone, PCT is physiologically inert. However, bacterial endotoxins (notably LPS) and proinflammatory cytokines such as IL-1, IL-6, and TNF-α stimulate production of PCT from extra-thyroid tissues, including most intra-abdominal organs and leukocytes [5,13,25].

Unlike CRP, PCT undergoes different regulation by pro-inflammatory cytokines, likely owing in part to its extra-hepatic production.

  • Cytokines like IL-1, IL-6, and TNF-α upregulate production of CRP, ESR, and PCT [13,25].
  • IFN-γ, the predominant cytokine in viral infections, is thought to downregulate PCT production, whereas it leads to upregulation (albeit more mild) of CRP and ESR. As a result, PCT is thought to be significantly lower in viral infections [13,25].
  • Notably, PCT is not elevated in noninfectious inflammatory conditions including most rheumatological diseases, gout, SLE, and IBD. However, PCT can be elevated in severe trauma, such as burns or surgery [5,25].

Kinetics & Reference Range: Normal serum levels of PCT are < 0.05 ng/mL. PCT levels become detectable around 3–4 hours and peak within 6–24 hours, which is earlier than both CRP and ESR. The half-life is around 24 hours which is the rate it is cleared when the stimulus is removed [5,25]. Unlike CRP, renal function is a major determinant of PCT levels [19].

  • Under 0.1ng/mL is thought to be a strong negative predictor of bacterial infection (i.e. bacterial infection unlikely). Generally, a value between 0.5 and 1.0 is picked as a cutoff range for bacterial infection, with values between 0.1-0.5 being indeterminate [5,13,25]. However, these ranges have not been consistently validated to predict bacterial infection.

Clinical Applications

  • CRP and ESR are non-specific inflammatory biomarkers that will be elevated in the setting of any significant inflammation, so they cannot be reliably used to diagnose any specific disease [2-5,12-14,16-22,26]. However, these markers can aid in Bayesian reasoning to shape pretest/posttest probability or provide adjunctive information when searching for unusual diagnoses [2-4,20,26-27]. 

  • While PCT may be more specific for bacterial infections, it is flawed by still being rather non-specific and is not validated as a stand-alone diagnostic criteria for infection in the setting of the emergency department. Like the other two inflammatory markers, it still may be used to help shape pretest/posttest probability for infection [26-27].

  • A 2017 review in the American Journal of Emergency Medicine reiterates that no single inflammatory markers (including CRP, ESR, and PCT) can be used as a stand-alone test to confirm or exclude infection, but instead advocates for using the tests as adjunctive information for emergency physicians to shape their pre-test probability of infection [26].

Specific Evidence:

Septic arthritis: 

    • According to the European Journal of Bone and Joint Infection’s 2023 guidelines for septic arthritis of native joints (SANJO), no blood tests have adequate sensitivity or specificity to either diagnose or exclude SANJO. A weak recommendation based on very low quality evidence was made for using CRP to guide diagnosis and treatment. They recommend synovial joint aspiration and analysis for bacteria (and leukocytes) to diagnose SANJO [28]. Synovial aspirate with > 50,000 WBC and 90% neutrophils strongly suggests a bacterial source [29].

    • A 2011 meta-analysis in the journal of Academic Emergency Medicine found ESR, CRP, and PCT were not acutely useful in the diagnosis of septic arthritis due to wildly varying sensitivities and specificities between studies. They recommended synovial fluid analysis as essential to the diagnosis [30].

    • A 2015 prospective, cross-sectional study of 78 Thai patients published in the International Journal of Rheumatic Disease demonstrated a sensitivity of 59% and specificity of 84% for PCT with a cut-off of 0.5 ng/mL, noting the seven prior, similarly powered studies investigating PCT for diagnosing septic arthritis had similar specificities between 80-100%. They suggested using PCT to help rule-in septic arthritis, particularly if synovial aspiration was unavailable [31]. However, these observations have failed to be validated at a larger level and should be taken with caution.

Orthopedic infections:

    • ESR and CRP have okay screening capabilities for orthopedic infections. A 2020 meta-analysis of 16 orthopedic studies including a total of 2,941 patients, found that an ESR cutoff of 30mm/hr demonstrated pooled sensitivity of 78% and specificity of 68%; a CRP cutoff of 10.8mg/L demonstrated pooled sensitivity of 79% and specificity of 70%; combined ESR and CRP demonstrated pooled sensitivity of 83% and specificity of 72%. Notably, this meta-analysis had very high heterogeneity as the studies involved different orthopedics infections, such as osteomyelitis, prosthetic joint infections, and septic arthritis [4].

    • The 2019 Journal of Arthroplasty practice guidelines to screen for periprosthetic joint infections recommend using ESR at 30mm/hr and CRP at 10mg/L, citing pooled sensitivities and specificities ranging from 75%-86% and 70-72.3%, respectively, for ESR and 88% and 73-74%, respectively, for CRP [32].

Spinal Infection:

    • According to the Infectious Disease Society of America’s (IDSA) 2015 guidelines for native vertebral osteomyelitis, CRP and ESR in the setting of protracted back pain have sensitivities ranging from 94 to 100% for ruling out infection and malignancy in these patients. While they are not specific, significant elevations in the setting of back pain should raise suspicion for spinal infection or neoplasia. Notably, up to 40% of patients with native vertebral osteomyelitis had a normal WBC [33-34].

    • A 2008 review in the International Journal of Medicine on spinal epidural abscess (SEA) agreed that inflammatory markers (specifically ESR and CRP) are generally sensitive in the diagnosis of SEA, but are not specific. An ESR > 20 mm/h was found in 95% of cases. They noted a leukocytosis is only present in 60-80% of cases [61].

      • Interestingly, there are no meta-analyses regarding the sensitivity of inflammatory markers for SEA. Most of the literature are case reports from the 1990s or earlier, many of which were internationally studied, where ESR was more readily available than CRP.

Bacterial Meningitis:

    • IDSA guidelines for 2004 report that a normal CRP value has a high negative predictive value for bacterial meningitis, but sensitivities and specificities vary between studies [35]. 

    • A 2015 meta-analysis of 9 studies consisting of 725 patients published in the International Journal of Infectious Diseases found PCT far superior to CRP, with PCT having a sensitivity of 90 and specificity of 98% [36].

Infective Endocarditis

    • Inflammatory markers are not part of the Duke Criteria for infective endocarditis, which are the universally accepted diagnostic criteria. According to the Duke Criteria, the major criteria involve evidence of bacteremia and evidence of endocardial involvement, such as an echocardiogram demonstrating vegetation or new valvular dysfunction. Incorporation of inflammatory markers into the Duke Criteria as minor criteria has been proposed, but not accepted [37].

    • Significantly elevated CRP (>122mg/L) and PCT (>0.5ng/mL) levels are predictors of bad outcomes, and are useful for tracking therapy progress, but are not specific enough to rule-in infectious endocarditis [38-39]. Similarly, a 2013 meta-analysis of 6 studies with 1,006 patients published in the American Journal of Emergency Medicine showed neither CRP nor PCT are sufficient to rule-in or rule-out infective endocarditis, with PCT having a pooled sensitivity of 64% and specificity of 73% and CRP having a pooled sensitivity of 75% and specificity of 73% [40].

Inflammatory Bowel Disease

    • Fecal calprotectin (FC) is more reliable than CRP at predicting IBD (both CD and UC). FC > 300 ug/g have 89% sensitivity and 83% specificity for IBD, making it a very useful tool to screen for IBD. Compared to CRP, FC has similar sensitivity but nearly double the specificity [42-43]. 

Pneumonia

    • A 2020 meta-analysis of 8 studies including 2,215 adults with confirmed community acquired pneumonia in different settings found PCT with a cutoff of 0.5 ng/mL had a pooled sensitivity and specificity of 55% and 76%, respectively [44].

    • A larger 2022 meta-analysis in the journal of Clinical Microbiology and Infection examined different test modalities for diagnosing pneumonia in the setting of clinical suspicion for acute community-acquired lower RTI in outpatient clinics, LTACs, and the emergency department. In 15 studies with 5191 patients, CRP with a cut-off >50mg/L had pooled sensitivity of specificity of 75% and 75%. In 7 studies with 4164 patients, PCT with a cut-off > 0.1 ng/mL had identical pooled sensitivity and specificity of 75% and 75% [45].

      • In 86 studies including 88,423 adults and children, the history finding of a cough had a sensitivity approaching 90%, but the specificity of cough ranged from 14%-23%.

      • In 13 studies including 1,567 individuals (78% adults, 92% ED setting), chest X-ray also had pooled sensitivity and specificity of 75% and 75%.

      • Notably, lung ultrasound for the diagnosis of bacterial CAP demonstrated exceptional stand-alone diagnostic accuracy in 33 studies including 4,901 adults and children in the emergency department, with a pooled sensitivity of 92% and specificity of 90%. This finding was not significantly different among operators with different levels of experience, or between adults and children.

      • The authors recommended against the use of biomarkers or clinical symptoms stand-alone tests to diagnose bacterial pneumonia given the poor test characteristics. Instead, they strongly advocated for the use of lung ultrasound to diagnose bacterial CAP [45].

    • PCT levels have been proposed as a way to differentiate bacterial from viral pneumonia and thus guide initiation of antibiotic therapy. However, the data does not support its use for this.The 2019 American Thoracic Society guidelines for CAP recommend initiating antibiotic therapy regardless of PCT levels, as the reported sensitivity of PCT for bacterial infection ranges from 38% to 91% [46-48].

      • PCT thresholds for guiding antibiotic therapy have been established to be < 0.1 ng/mL (strongly recommended against antibiotics), 0.1-0.25 ng/mL, 0.25-0.5 ng/mL, and >0.5 ng/mL (strongly recommended using antibiotics).

      • A 2018 USA multi-center prospective RCT involving 1,656 adult patients published in NEJM used varying PCT cut-offs to guide antibiotic initiation in the emergency department. It found no significant difference in antibiotic usage in the group using PCT compared to the usual care group [49].

      • A 2019 French multi-center prospective RCT involving 370 ED patients published in Annals of Emergency Medicine similarly found no difference in antibiotic exposure between PCT-guided versus usual care groups [50].

      • In contrast, an 2017 Cochrane Review update regarding using PCT to initiate or discontinue antibiotics found PCT-guided therapy had a statistically significant decrease in mortality for hospitalized patients by 1.4% (primary endpoint) and a statistically significant decrease in antibiotic exposure by 2.4 days (secondary endpoint) [51].

Sepsis

    • PCT may have some utility in guiding posttest probability for sepsis when the diagnosis is unclear. A 2013 meta-analysis of 30 studies including 3,244 patients published in The Lancet found PCT to have a pooled sensitivity of 77% and specificity of 79% for sepsis in critically ill patients [52]. A 2019 meta-analysis of 19 observational studies including 3,012 patients published in the Journal of Intensive Care found PCT to have a pooled sensitivity of 80% and specificity of 75% for the diagnosis of sepsis; this study also found presepsin, a newer biomarker, to have comparable sensitivity and specificity to PCT [53].

    • Despite these results, the 2021 Surviving Sepsis guidelines recommend against using PCT to guide initiation of antimicrobial therapy due to multiple meta-analyses demonstrating no improvement in outcomes using PCT-guided antibiotic therapy [46,54].

Rheumatologic disease:

    • Elevated ESR and CRP are important diagnostic criterion for temporal arteritis and polymyalgia rheumatica [21], but more recent studies have demonstrated ESR can be within the normal range in around 20% of these patients [55-57] whereas CRP is usually more reliable [58-59]. 

    • According to a 2014 review in the Journal of Rheumatology, PCT may be useful to determine the presence of bacterial infection in patients with rheumatologic disease because it is highly specific for bacterial inflammation, although it lacks sensitivity and should not be used to rule-out bacterial infection. PCT cut-offs vary depending on the type of infection [60]

Post by Eric Segev, MD

Dr. Segev is a PGY-1 in Emergency Medicine at the University of Cincinnati

Editing by Melanie Yates, MD and Ryan LaFollette, MD

Dr. Yates is a PGY-4 and Chief Resident in Emergency Medicine at the University of Cincinnati. Dr. LaFollette is an Associate Professor of Emergency Medicine and Co-Editor of TamingtheSRU.com

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