Inflammatory biomarkers: CRP, ESR, Pro-Calcitonin
Summary
Some of the inflammatory biomarkers we commonly test for are CRP, ESR, and PCT. PCT is more sensitive and more specific than CRP, however much more costly.
Introduction
Inflammation is a complex process whereby biochemical and cellular events occur in order to remove tissue debris and foreign organisms. Inflammation has local and systemic changes ( called the acute phase response ). During this acute phase response, there is an increase in the synthesis of proteins called acute-phase proteins. These proteins are produced in the liver. These proteins usually increase by 25% or more following inflammation. These proteins can be classified into Group I (C3, C3, Ceruloplasmin), Group II (Alpha1-antitrypsin, Haptoglobin, Fibrinogen), and Group III (C-Reactive Protein, Serum Amyloid A). Group I has a 0.5x increase, Group II has a 2-4x increase and Group III has a 1000x increase.
Other proteins, will decrease in concentration rather than increase. This occurs because these proteins are redistributed in the extravascular space or they are not produced as much during inflammation. These include Albumin, Pre-albumin, Transferrin, Retinol binding protein, and Alpha and Beta lipoprotein.
The main production of these proteins can be divided into hepatic and extrahepatic production. The majority of the proteins are produced in the liver. The main cytokine responsible for the acute phase response is interleukin-6.
C-Reactive Protein
This protein binds to the phosphoryl-choline in the cell walls of bacteria. It also binds to damaged tissues and also to DNA (nuclear debris) that has been released from damaged cells. After it binds to these structures, it helps with the activation of the complement pathway.
CRP is ideal for the diagnosis of acute inflammation and to monitor all inflammatory diseases. However, a normal level does not exclude inflammation. For instance, localized disease, recurrent attacks of inflammation, and mild chronic tissue damage may not raise the level of CRP very much. When the CRP level is > 100mg/L it is strongly suggestive of a bacterial infection.
Has a short half-life, hence helpful for acute inflammation. It is very sensitive, specific, and early to respond.
Ranges:
| Reference | 3 – 10mg/L |
|---|---|
| Mild Inflammation (Influenza) | +/- 40mg/L |
| Active Inflammation/Bacterial Infection | 40 – 200mg/L |
| Serious Bacterial Infection | Up to 500mg/L |
Other causes of raised CRP: CRP rises 6 hours after a skin incision (surgery) and peaks at around 48 hours, and it falls with a half time of 24-48 hours. Thus, should be completely lowered back to normal in around 5-10 days. If the patient develops a surgical complication (wound infection, abscess, tissue necrosis, thromboembolism) then this will result in a raised CRP.
Erythrocyte Sedimentation Rate (ESR)
An erythrocyte sedimentation rate (ESR) is a type of blood test that measures how quickly erythrocytes (red blood cells) settle at the bottom of a test tube that contains a blood sample. Normally, red blood cells settle relatively slowly. A faster-than-normal rate may indicate inflammation in the body. Inflammation is part of your immune response system. It can be a reaction to an infection or injury. Inflammation may also be a sign of chronic disease, an immune disorder, or other medical condition.
This test measures how quickly the “erythrocytes” settle at the bottom of the test tube. This is measured over a period of one hour. The distance that the erythrocytes fall in this test tube due to gravity is measured in mm. Hence, ESR is measured in Xmm/hour. This process of settling or falling is called sedimentation.
During the process of inflammation, acute phase proteins such as fibrinogen, increase in the blood. This results in the erythrocytes becoming more “sticky”. They will sediment quicker and hence they will drop to the bottom of the test tube quicker. Hence, conditions such as infections, cancer, or autoimmune conditions RAISE the ESR. Conditions that prevent the erythrocytes to drop to the bottom of the tube include Polycythemia, Hemoglobinopathies (Sickle Cell Disease), and Abnormal cell shape (Spherocytosis). These conditions can DECREASE the ESR.
The range of ESR depends on age and gender. However, it should be around < 20 mm/hr in adults and <10 mm/hr in children.
ESR can be affected by many conditions and hence it is not very sensitive or specific. Any process that elevates fibrinogen (e.g., pregnancy, infection, diabetes mellitus, end-stage renal failure, heart disease, malignancy) may also elevate the ESR.
The ESR starts rising after 3-4 days and then it goes back to normal around 3-4 weeks.
Has a longer half-life, and hence better to assess chronic inflammation. It has a high sensitivity but has lower specificity than CRP.
False Positive/Negative: Anaemia, Abnormal RBCs, Age, Pregnancy
Ranges: A level greater than 100mm/1 hour usually indicates underlying malignancy, acute infection, or connective tissue disease
Pro-Calcitonin (PCT)
This is a precursor of calcitonin. Calcitonin is a calcium regulatory hormone. The production of PCT is from the thyroid C-cells. During sepsis, Calcitonin may also be produced from other sites such as the liver, kidney, pancreas, adipose tissue, and brain. PCT takes around, starts to rise at 4 hours, and peaks at around 6 hours and 2-3 days to go back to normal. This means that PCT goes back to normal 2-3 days earlier than CRP. PCT is more sensitive and specific than CRP. It is also much more expensive. It is usefu to differentiate systemic bacterial infection from noninfectious systemic inflammatory response syndrome (SIRS). The levels are not raised by viral infections.
| Condition | Level |
|---|---|
| Systemic bacteria infections, MOF | >10 ug/L |
| Sepsis | 2 – 10 ug/L |
| Sepsis, to rule out other conditions | 0.5 – 2 ug/L |
| Sepsis unlikely, rule out localized infections | < 0.5 ug/L |
PCT may be used to decide when to stop antibiotics at an earlier time. Especially when the PCT is very low or remains low. When the PCT drops below <0.5ng/ml or it has dropped >80% from its peak level then it is said that antibiotics for a systemic/non-localized infection can be stopped.
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