Abstract
Calprotectin is an acute phase reactant. It is the dominant cytosolic protein in neutrophils and is also present to a lesser extent in monocytes and macrophages. Plasma concentrations increase five- to forty-fold following infection or inflammation, but faecal concentrations are about six times higher than those in plasma. 1,2
Investigations have shown that faecal calprotectin is effective in directly assessing intestinal inflammation. It correlates well with measures of intestinal permeability, 111Indium-labelled white cell scanning and endoscopic grading of inflammation. 1,2 As such, it has been investigated for use in the differential diagnosis of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).
Physicians are commonly faced with the problem of distinguishing between these two conditions. IBS is a functional bowel disorder affecting 10–20% of the population and is characterized by abdominal pain, bloating, excessive flatulence and/or change in bowel habit. Symptoms are similar to those of IBD, a more serious condition requiring different treatment. Differentiating the two conditions often requires referral for expensive, costly, invasive and time-consuming endoscopic and/or radiological investigations where up to 87% of investigations can be negative. 3
What is needed is a relatively cheap and effective method to rule out IBD. Faecal markers including calprotectin, lactoferrin, myeloperoxidase, lysozyme, S100A12, alpha-1 antitrypsin and neutrophil elastase and serological markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), antisaccharomyces cerevisiae antibody (ASCA) and antineutrophil cytoplasmic antibody (ANCA) have been tested for their ability to distinguish between IBD and IBS, with the majority of studies focusing on calprotectin.
Two recent articles commissioned by the NHS Centre for Evidence-Based Purchasing have advocated its use for this purpose but with some reservations. 4,5 They quote a number of studies where positive and negative predictive values varied from 60–100% depending on the nature of the study population. However, they report that where likelihood ratios were available, they were below the >10 (likelihood ratio for a positive result (LR+)) and <0.1 (likelihood ratio for a negative result (LR−)) limits defining a good diagnostic test. In contrast, a rigorous meta-analysis in the British Medical Journal found sensitivity/specificity for adults of 93/96% and children 92/76%, respectively. Likelihood ratios were 20 (LR+) and 0.05 (LR−) for adults and 5 (LR+) and 0.1 (LR−) for children. 6
Despite this interest over the past few years, faecal calprotectin is yet to be mentioned in a series of guidelines relating to the investigation of IBS and IBD, with recommendations limited to performing non-specific inflammatory markers like CRP and ESR prior to referral. 7–9
Calprotectin can be measured by enzyme-linked immunoassay (ELISA) using one of the two available methods: PhiCal (Calpro AS, San Diego, CA, USA) and EK Cal (Alpha Laboratories Hampshire, UK) or more recently by point-of-care testing (POCT) devices, Prevent ID CalDetect and Quantum Blue (both marketed in the UK by Alpha Laboratories). The latter may provide a more cost-effective alternative for laboratories that either lack the capability or do not have sufficient numbers to warrant running their own ELISAs. Although shown to correlate well with existing ELISA methods, there is little clinical data on the value of such tests.
The primary and most productive area for cost-saving, however, is theoretically in the primary care population, where ruling out IBD would result in a reduction in the number of patients referred to secondary care for investigation. Although found to be cost-effective by the NHS study using a hypothetical model, there has been no verification of the true effectiveness of calprotectin in this group of patients – diagnostic accuracy figures used in the costing study were taken from a study of patients at secondary referral. 4,5 In their model, they also suggest that it is likely that patients with calprotectin values between 50 and 250 μg/g will have a repeat calprotectin test rather than referral. This may have significant impact on the laboratory calprotectin workload.
What about the use of a panel of markers to rule out IBD? Will this be more cost-effective than a single biomarker? 10 Will the advent of POCT devices for calprotectin enable testing to move out of the hospital laboratory setting and into the community? The POCT devices still require stool extraction which can be performed without a centrifuge but do require accurate pipetting. How would this affect assay performance?
What is needed is a large multicentre-based study in a primary care population looking at a larger panel of potential markers to determine the cost-effectiveness, best diagnostic cut-off and markers for use in ruling out IBD. Until this is done, no amount of meta-analyses will be able to fully answer these remaining questions.
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