CRP - the most overused and overrated test of all time?

Most days it feels like half the calls I get as a consultant microbiologist are from junior doctors who are worried because a patient's CRP has gone up. My cure for that problem is to tell them to stop measuring it. CRP used to be a test that was used carefully. It is now used as part of routine monitoring. There are calls to use it as a rule out test for sepsis in primary care. So what is the performance of this test for detecting significant infection in the real world?

We have looked at the ability of CRP to predict bacteraemia, which is probably a reasonable proxy measure of sepsis. We looked back at all blood cultures sent to our lab between Jan 2011 and August 2017. This identified 36396 sets of cultures, of which 32703 were negative, 1210 grew a likely contaminant, 1800 grew a likely pathogen and 683 grew an organism isolated in a duplicate set. We then linked this data with concurrent laboratory requests for a CRP. The number of specimens with a CRP measured within 7 days were : 29403 (90%) for negative; 1063 (88%) for contaminant; and 1699 (94%) for an isolated pathogen.

Figure 1 shows the day of the peak CRP measured in the episode. We can see that in episodes with proven infection, there is a lag to peak CRP.

fig.1 Day of peak CRP

We then looked at how the initial CRP predicts bacteraemia. Figure 2 shows the cumulative percentage of episodes in each category at increasing CRP cut-offs (in other words, the number of episodes that would be missed for a particular cut-off CRP value). We can see that 30% of cases of significant bacteraemia have a CRP below 50 on presentation, and over 50% have a CRP below 200.

fig 2

The small difference in the curves for the three categories also suggests that initial CRP is not good at discriminating between infection and not infection. We can see this if we plot a receiver-operator curve (fig 3). In a ROC, a test with no value shows a straight line, whereas a good test has a hyperbolic distribution. The initial CRP looks very straight on the ROC. You can draw your own conclusions about the performance of the initial CRP in predicting bacteraemia.

fig 3. ROC for initial CRP in predicting bacteraemia

We then repeated the analysis for the peak CRP measured in the week after the blood culture draw. (fig 4 and 5). So it performs a bit better than the initial CRP, but not a lot.

fig 4

fig 5. fig 3. ROC for peak CRP in predicting bacteraemia

So this is my main conclusion :

It is not possible to find a cut-off value for CRP that tells you anything meaningful about the probability of bacteraemia

We can probably also conclude that there is often a delay between onset of serious infection and rise in CRP. So CRP is really bad at telling us what is going on in an acute setting.

Why are people pushing CRP then? I guess when it was carefully performed in selected cases when it was first brought in as a test, it was quite useful. We can see from our data that there is some signal there, but it's drowned out by noise.

I also suspect that in most cases a CRP is telling us absolutely nothing, but we are using the result to justify our decision making. When it suits us and it confirms our prejudice. Of course, the problems come when there is a mismatch between these two things. People cope with this dissonance in many ways. The most annoying of which is to phone the microbiologist. The most dangerous of which is to make an inaccurate diagnosis.

Antibiotic resistance is a distraction in community onset sepsis

1. Sepsis usually presents rapidly. Most patients with sepsis know that they are seriously unwell, and go straight to the ED, without presenting to primary care in the preceding days. Sometimes this involves a telephone triage by 111. Occasionally there is a prior review by a primary care doctor. This process appears to work well.

2. There are occasional cases which present more insidiously to primary care in the days preceding onset of sepsis.

These are harder to recognise and do not fall into patterns that are easy to define. Here, clinical judgement is crucial and should be valued and supported. Protocols for recognition of sepsis do not seem to translate easily into primary care, and we should be wary about adopting guidance in which secondary care based assessment protocols have been adapted according to expert opinion with no evidence base. Local practitioners felt that following rigid protocols in primary care could lead to overdiagnosis of sepsis, particularly in self-limiting viral illness. However, they also voiced concerns around medicolegal issues that may result from not following these protocols. Our cases also show that sepsis presents in ways that may be missed by secondary care protocols. Our cases suggest some features of severe infection that practitioners should be aware of when assessing patients in primary care, such as change in mental state and history of rigors. Current body temperature seems unhelpful. These observations fit well with recommendations in some scoring systems (eg. qSOFA). There may be a need for better rapid diagnostics to support clinical decisions. However, we noted that 19 of the 50 patients had a CRP below 100 on admission to the ED. We also saw that white blood cell counts were frequently normal. We did not examine the potential benefit of other inflammatory markers (eg, procalcitonin). There may be constellations of common tests that add value to the diagnostic and therapeutic processes. For instance, 12 patients had evidence of acute kidney injury on admission. This is likely to be important in determining severity and prognosis.

3. We need to recognise the importance of good quality care for chronic disease. 

eg. Diabetes, ulcers, catheters. Good management of these conditions is likely to reduce the incidence of downstream problems, including sepsis. We noted that care of these conditions is becoming fragmented, falling between different agencies (eg. doctors, community nursing, practice nursing, specialist nursing, care homes) and we often saw a lack of joined up care planning. In addition, despite the high prevalence of these problems, there is often a lack of evidence on which to base decisions (for example, prevention and management of catheter blocking). We may also need to consider more innovative models of care delivery for these patients. For instance, “leg clubs” have been set up for patients with chronic leg ulcers to encourage mutual support . Such psychosocial approaches may be more effective in persuading patients who struggle with compression to persevere with a treatment that is effective but uncomfortable.

4. There are a group of recurrent /chronic infections for which we lack good guidance on management.

Eg. UTI in men / recurrent UTI / cellulitis in ulcers / vaccine preventable pneumococcal infection in chronic lung disease. We need to develop new approaches to these. Some simple key primary care messages may help, for instance, around appropriateness of patient directed self-start antibiotics in recurrent UTI 7 and clearer guidance on when patients should be referred for investigation of underlying problems, such as urinary retention. A further problem in these cases is loss of continuity of care. When episodes of infection are relatively infrequent, we saw that each episode tended to be treated in isolation. A loss of continuity of care has been identified as a factor leading to hospital admission. We need to find ways to compensate for these changes to healthcare delivery, and, for instance, laboratories may be well placed to identify and alert carers to emerging patterns.

5. There is an ongoing need to ensure that microbiological diagnostics are aligned to clinical need.

Currently, diagnostics are significantly compromised by the poor quality of specimens that are received in the laboratory. The importance of this is illustrated by a case in our series of Group B streptococcal infection from an infected ulcer. Laboratory standard procedures target S. aureus and Groups A, C and G haemolytic streptococci from superficial wound swabs. It is hard to determine what is pathogenic in these specimens, which are often of low quality and lack clinical details, and this can lead to overtreatment of colonising flora. Improved swab methodologies (eg. debridement prior to sampling) may enable better discrimination between pathogens and colonising organisms.

6. Antibiotic resistance (in this series at least) was a minor reason for development of sepsis. 

We saw four cases of potentially avoidable admission in which the organisms were resistant to empirical (guideline) antibiotics. However, in two cases, it is extremely doubtful that antibiotics in the community could have altered the natural history, and in all cases it was hard to imagine alternative and reasonable empirical options in the absence of specific sensitivity data. We need to consider how diagnostics can support early detection of important resistance in primary care.

Laboratory accreditation as a lever for adding value to pathology services