Understand the Optimal Use of Inflammatory Marker Tests

Dr Peter Saul Explains the Role of Common Tests for Inflammatory Marker in Primary Care, Emphasising the Importance of Their Careful Application and Interpretation

According to a 2014 report by NHS England, as many as 40% of pathology tests ordered by clinicians working in the NHS are unnecessary.¹ The same report states that an estimated 130 million haematology tests are performed each year.¹ Tests for inflammatory markers are just one of the many types of haematology test commonly ordered by primary care clinicians. Evidence suggests that the use of inflammatory marker tests is rising; in particular, there was a consistent linear increase in the use of C-reactive protein (CRP) tests between 2000 and 2015.² At a time of continued budgetary and workforce constraints, it may be helpful for GPs to understand the primary uses of the different tests available for inflammatory markers, especially as some clinicians have expressed uncertainty about their appropriate use.³

GPs can specifically request estimation of one or more of the three most commonly used inflammatory markers—CRP, erythrocyte sedimentation rate (ESR), and plasma viscosity (PV)—or they may be estimated as part of a routine blood test. Testing for these inflammatory markers gives a measure of a person’s acute-phase inflammatory response,⁴ but their lack of specificity can make interpretation difficult.⁵ Therefore, these tests may be more useful for detecting acute inflammation indicative of an already‑suspected disease, and for ruling out specific conditions, than as general diagnostic tools.⁵

Levels of CRP, ESR, and PV are usually elevated when the inflammatory response is activated, which occurs in three principal situations:⁵

• infection
• autoimmune disease
• certain types of cancer.

Active phases of chronic inflammation, acute tissue damage, and physical injury are other potential causes of elevated CRP, ESR, and PV levels.⁶

This article will discuss these three inflammatory marker tests, explaining how they work, what constitutes a normal result, how to interpret abnormal findings, and the potential of point-of-care CRP testing.

C-reactive Protein

C-reactive protein was first discovered in 1930, and is so named because it reacts with the C carbohydrate antigen of the capsule of Streptococcus pneumoniae.⁷ It is synthesised by the liver, and induced by interleukin-6 produced during the acute phase of inflammation or an infection.⁷ CRP level changes rapidly in line with the status of the inflammatory stimulus, and a very high level is usually associated with an infection.⁷ If CRP level is persistently elevated, the cause may be a chronic inflammatory condition—including chronic infections, such as bronchitis or hepatitis—or an inflammatory arthritide, such as rheumatoid arthritis.⁷ Minor elevation in CRP level can also be associated with many conditions, including obesity, pregnancy, depression, diabetes, and cardiovascular disease.^7,8

In certain situations, CRP testing is preferable to PV testing: compared with PV, CRP level usually rises at an earlier stage in an infection (at around 6–10 hours) and has a shorter half-life (around 48 hours), so it can be particularly useful as early evidence of a bacterial infection.⁴ CRP also tends not to be elevated in viral infections, leukaemia, lymphoma, or connective tissue disease, so it can be used in patients with these conditions to monitor bacterial infection.⁴

Erythrocyte Sedimentation Rate

ESR is the rate at which red blood cells fall in a standardised tube, and it is influenced by the extent to which proteins are present in the blood.⁹ ESR is measured by calculating the distance in millimetres travelled in 1 hour by erythrocytes settling in anticoagulated blood owing to the influence of gravity. When the concentration of proteins in the blood increases, such as when acute‑phase proteins are induced by an infective or inflammatory condition, distinctive stacks of red blood cells form, termed ‘rouleaux’, in which the cells are clumped together like coins.^9,10 These rouleaux make red blood cells fall at a faster rate than if they remained separate, indicating the presence of an infective or inflammatory condition.^9,10

ESR is considered the least specific inflammatory marker, as it is affected by more factors than PV and CRP.^11,12 ESR is particularly affected by age and sex, as well as by haematocrit, lifestyle variables (such as alcohol consumption and regular physical exercise), and common metabolic differences (such as hypertension).¹²

In most circumstances, PV is a more reliable marker than ESR, so ESR testing will not be necessary.¹³ However, there are situations in which ESR is a useful indicator, such as in the management of polymyalgia rheumatica and temporal arteritis, as well as in the monitoring of certain biological therapies (for example, anti‑tumour necrosis factor therapy).¹³ Other benefits of ESR testing include its low cost and reproducibility.⁹

Plasma Viscosity

A PV test measures the thickness of a person’s blood plasma, which is primarily dependent on the concentration of plasma proteins (especially Fibrinogen and some immunoglobulins) in their blood.⁶ These proteins can increase in concentration for various reasons, most commonly as a result of infection, neoplastic disease, or inflammatory disease.⁴

Unlike ESR, PV is not affected by anaemia,⁴ nor by age, sex, or polycythaemia.¹⁴ However, obesity is associated with raised PV and raised blood viscosity in general, a link that may be explained by higher insulin resistance and an increased Fibrinogen level.¹⁵ Because it is more technically challenging to conduct a PV test, certain NHS laboratories may not offer it.¹⁶

Reference Ranges

Tables 1–3 outline the reference ranges for CRP, ESR, and PV, with suggestions of potential causes of elevated levels. These ranges will vary according to laboratory, and depend on local populations, technologies, and measurement techniques. Use of clinical judgement is advised when interpreting any results.

Interpreting Incidental Raised Levels

Interpreting a raised inflammatory marker level is easier when there is a pretest hypothesis that is being tested—indeed, this is the recommended use of inflammatory marker tests.^5,7 If the raised level is an incidental finding, however, the situation is less straightforward, and the following actions should be considered:

• think about whether a minor elevation may be a ‘normal’ variation (see Tables 1–3) or has a clinically insignificant cause⁷
• be aware that the likelihood of underlying disease increases as inflammatory marker levels increase⁵
• undertake a systemic investigation,^5,7 focusing on infection, autoimmune conditions, and malignancy
• if indicated, examine the patient and investigate according to findings⁵
• if history and examination do not suggest a particular cause, it is reasonable to wait and see if symptoms develop rather than conduct an extensive search for occult disease.⁵

Point-of-care Testing for CRP

Certain European countries, notably the Netherlands, have implemented point-of-care testing for CRP in primary care to help guide antibiotic therapy for acute respiratory infections.¹⁹ This testing has the potential to safely reduce antibiotic prescribing in these situations, as it can aid risk classification of patients with acute cough and suspected chronic obstructive pulmonary disease (COPD).^19,20 In the UK, CRP testing (when available) forms part of NICE’s recommendations on the diagnosis and management of pneumonia, which suggest delayed antibiotic prescriptions for patients with CRP values of between 20 mg/l and 100 mg/l, and immediate antibiotic prescriptions for patients with CRP values in excess of 100 mg/l.²¹ CRP testing is also the basis of the Primary Care Respiratory Society’s CRP point of care testing guideline, which is intended to guide the management of patients with and without COPD in whom respiratory infections are suspected.¹⁹

Unfortunately, point-of-care CRP testing is not generally funded at present, and there is uncertainty about its cost effectiveness. In the evidence review for NICE’s 2014 pneumonia guidance, the Guideline Development Group estimated that CRP tests would be cost effective at a threshold of £20,000 per quality‑adjusted life year, providing that they continue to cost less than £15.13.²² However, this conclusion is based on limited data, and there are significant upfront costs associated with setting up a point‑of‑care testing system.¹⁹

Summary

For tests that often have low specificity, it is important to select the correct test and be familiar with the implications and limitations of the result. Abnormal results will need to be viewed in the context of clinical findings, and will often lead to further investigation.