Working in the ED one day you seem to hit a run of patients in whom consultants have asked you to order an ESR, CRP. First, podiatry asked for them for a patient with 1st metatarsal osteomyelitis. Spine surgery wanted the same for a patient with diskitis. And, orthopedics wanted them for a possible septic. You think to yourself, “what am I or my consultant going to do with these test results?” “What are these inflammatory markers anyhow?” And, “what patients should I be ordering them in.”
What are Acute Phase Reactants?
Acute phase reactants (APR) are proteins that increase or decrease in the setting of inflammation and tissue injury. These changes are primarily due to hepatocyte production in response to cytokines produced by the host’s immune system. The physiologic function of acute phase proteins is largely believed to be beneficial to the host in identification and elimination of the insult and to aid in healing or adaptation. We are more specifically interested in proteins whose concentrations change at least 25% in the setting of clinically significant insults. We measure the concentration of the acute phase proteins, either directly or indirectly, with tests referred to collectively as acute inflammatory markers. There are caveats to all of this, of course. Despite their name, acute phase reactants increase in both acute and chronic inflammation and injury. This is part of the reason that interpreting acute inflammatory marker results can sometimes be so difficult. The acute inflammatory markers covered in this post will be C-reactive protein, erythrocyte sedimentation rate, and Procalcitonin.
C-reactive protein is a positive direct inflammatory marker. In settings of inflammation, cytokines induce hepatocytes to produce CRP, which itself promotes recognition and elimination of noxious stimuli. It does so by binding phosphocholine on the surface of damaged tissue and pathogens, promoting phagocytosis, and activating the compliment system. CRP begins to rise within 4-6 hours after the onset of inflammation and peaks within 36-50 hours. CRP has a half-life of 4-7 hours; therefore, serum levels are a measure of active inflammation (1). Because CRP rises quickly and has a short half-life, it can be a useful measure for diagnosis and response to treatment (14).
An elevated CRP level indicates some level of active inflammation, but that in itself is not entirely helpful. The downside of CRP is its lack of specificity. Many things that cause cellular stress (obesity, smoking, diabetes, hypertension, fatigue, depression, advanced age, and many others) cause some elevation in CRP concentration (12). However, 88–94% of patients with a markedly elevated CRP concentration (> 500 mg/L) have a source of bacterial infection (21). Because CRP is produced in the liver, falsely reassuringly low CRP levels can be seen in patients with hepatic failure (1).
Erythrocyte sedimentation rate is an indirect measure of acute phase reactants and is also a positive inflammatory marker. ESR is very simply the rate at which red blood cells settle in a vertical tube, measured in mm/hr. The rate of RBC sedimentation is affected by the constituents of the patient’s serum. The main acute phase reactant that causes an increased ESR is fibrinogen, but concentrations of other proteins such as immunoglobulins also contribute. Increased fibrinogen and other proteins cause RBCs to aggregate and settle faster. ESR typically begins to increase within 24 hours after the onset of insult. Because the half-life of fibrinogen is about 100 hours and that of IgG is more than a week, ESR can remain elevated for weeks after the initial rise (1).
ESR can be a useful tool to aid in the diagnosis and management of certain specific situations, but like CRP it lacks specificity. Marked ESR increases (>100 mm/hr) are associated most often with infection (33%) and neoplasm (17%), however end stage renal disease is also a significant cause (17%) (7). Age, female sex, and anemia are other non-inflammatory causes of increased ESR. There are additionally many reasons a patient might have a misleadingly low ESR. Abnormal erythrocytes, hypofibrinogenemia, polycythemia, and high serum bile salts are all causes of spuriously low ESR (11).
Procalcitonin is a peptide precursor to calcitonin that is released by various tissues in the body, primarily lung and intestine, in response to bacterial toxins and cytokines. Conversely, procalcitonin is downregulated during viral infections. The exact physiologic role of procalcitonin is not yet entirely known. Procalcitonin levels become detectable in patient’s serum as early as 3-6 hours after onset of inflammation and remain elevated for 12-36 hours after resolution (16).
Because concentrations of procalcitonin increase in response to bacteria and decrease in response to viruses, it is a particularly interesting acute inflammatory marker in the age of antibiotic resistance and the need for antibiotic stewardship. There have been many studies done to determine the utility of procalcitonin for this purpose with some encouraging evidence. This is a particularly expensive test, however, and is not available in all healthcare settings.
When Would I Order These Tests?
CRP, ESR, and procalcitonin each has utility and can be used in conjunction with the overall clinical picture to aid in evaluation and management in specific scenarios. None of these tests are specific to any particular process and should not be used in isolation, but there is evidence to suggest that they have value to add to clinical practice. Highlighted below are a few instances in which these tests can be useful.
Neonates and infants do not always manifest the typical signs and laboratory results of sepsis, therefore additional tools are often used to aid in the diagnosis and to monitor treatment. CRP and procalcitonin have both been studied for this purpose. Elevated CRP has been shown to be an independent predictor of serious bacterial infection in infants (3). CRP has been shown to have a high negative predictive value, especially when two levels are measured 24 hours apart, allowing for earlier cessation of empiric antibiotics (18). Procalcitonin has been shown to have similar diagnostic accuracy for serious bacterial infections and higher diagnostic accuracy for invasive bacterial infections compared to CRP (15).
As part of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scoring system, CRP has been used to distinguish necrotizing fasciitis from severe cellulitis or abscess. LRINEC uses CRP, white blood cell count, hemoglobin, sodium, glucose, and creatinine to determine whether a patient is low, moderate, or high risk for necrotizing fasciitis. A CRP of 150 mg/L or greater is given a score of 4, with a total score of 6 being the cutoff for high risk. This scoring system had a positive predictive value of 92% and a negative predictive value of 96% in the initial study (22). However, additional studies have found LRINEC to have inadequate sensitivity to rule out necrotizing fasciitis (5).
Spinal epidural abscesses and vertebral osteomyelitis/discitis are significant and increasing causes of back pain in the emergency department with potentially devastating consequences. The use of ESR and CRP can aid in the diagnosis and monitoring for treatment success. IDSA guidelines recommend obtaining ESR and CRP in patients with new or worsening back pain with suspicion for vertebral osteomyelitis. Elevated ESR and CRP in patients with back pain has a sensitivity between 94-100% for osteomyelitis, and thus a high negative predictive value (4). The sensitivity for spinal epidural abscess was similarly high (6). In the setting of back pain with an elevated ESR and/or CRP, urgent/emergent MRI should be obtained. In a patient with vertebral osteomyelitis, ESR and CRP can be used to monitor treatment success and persistently elevated ESR and CRP after 4 weeks of treatment should alert clinicians to treatment failure (4). Decreasing CRP can be used to indicate that it is safe to switch from IV to oral antibiotics.
While ESR (98%) and CRP (94%) have high sensitivity for septic arthritis, their lack of specificity limits their utility in the emergency setting (8). Therefore, treatment should be based on joint aspiration and synovial fluid analysis for gram stain, cell count, and bacterial culture.
Written by: Josh Gauger, MD
Peer Review and Editing by: Jeffery Hill, MD MEd
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