C-reactive protein (CRP) is the prototypical acute phase protein in humans 12. It is widely used as a marker of infection, and also to aid the differentiation between a bacterial and a viral origin. Many geriatricians have the clinical impression that the CRP response to serious invasive bacterial infections may be delayed in frail old patients. This view is not supported in the literature 1, but studies in this field are rather scanty. Some relatively small studies exist 345, but were not designed to compare the diagnostic sensitivity for bacterial infections in different ages, and do not give information on the proportion of false-negative tests.

CRP is mainly produced by the liver 6. The synthetic function of the liver may be reduced due to physiological aging, possibly due to both decreases in liver volume, liver blood flow and perfusion, and to cellular changes 7. The main stimulator of CRP synthesis in the liver is interleukin 6 (IL-6), which is associated with diseases of old age such as multiple myelomas, chronic lymphatic leukaemia and renal cancer 8, and is higher in older than in younger subjects 9. In mice the regulation of IL-6 synthesis is dependent of dehydroepiandrosterone, a hormone that declines with age, and the dysregulation is reversed by replacement of the hormone 10. Studies have found a delayed IL-6 response in infection in the old 11, as well as impaired production of proinflammatory cytokines 12. Thus, a diminished or delayed CRP response to bacterial infections in the old may be biologically plausible. The issue is clinically important, as the atypical clinical symptoms and signs of infection in geriatric patients make a correct diagnosis more dependent on a rational use of supplementary tests.

Hogarth et al suggest a cut-off value of CRP at 40 mg/L to be sufficient in elderly patients with infection 13, whereas one study has recommended that the cut-off value indicating sepsis, irrespective of age, should be 80 mg/L 14. Even higher cut-off levels are also commonly used in clinical decisions.

E. coli is the most frequent Gram-negative species in bloodstream infections 15, whereas S. pneumoniae is the leading cause of community-acquired pneumonia and a significant cause of bacteraemia and meningitis 16. Bacteraemia with either of these species will in almost every instance represent a clinically important invasive infection in need of antibacterial treatment. A "normal" CRP-concentration in these conditions can therefore be considered a false negative test result if CRP should be regarded as an indicator of bacterial infection.

The main aim of this study was to assess the diagnostic sensitivity of a raised CRP-concentration for bacteraemia with either E. coli or S. pneumoniae in different age groups. We also studied the impact of different cut-off points for the CRP-concentration as well as differences in the time course of the CRP-response in relation to age.

The study was approved by the Regional Committee for Ethics in Medical Research and by the Norwegian Data Inspectorate, which gave permission to carry out the study without the patients' consent.

1150 patients had a positive blood culture with either E. coli or S. pneumoniae during the study period. Of these, 260 had no registered CRP measurement on the same day as the blood culture, reducing the number of eligible patients to 890. Of these, 604 (68%) had had their blood culture and CRP drawn on the day of hospital admittance. 634 (71%) of the patients had E. coli whereas the remaining 256 had S. pneumoniae. Median age of bacteraemic patients was 75 years (IQR 58–82). 300 (34%) patients were < 65 years, 443 (49%) were 65–84 years, and 147 (17%) were ≥ 85 years. The percentages of E. coli in the three age groups were 61%, 77% and 76%, respectively (p =< 0.01), and the percentages of females were 58%, 50% and 71% (p =< 0.01), respectively. 421 control patients were eligible. Their median age was 77 years (IQR 62–83), which was significantly higher than in the bacteraemic group (p = 0.005). 120 (28%) of the controls were < 65 years, 223 (52%) were 65–84 years, and 84 (20%) were ≥ 85 years.

The median concentration of CRP on the same day as the positive blood culture (CRP1) was 188 mg/L (IQR 97–288 mg/L). For the control group taken together the median CRP concentration at admittance was 6 mg/L (IQR 2–19 mg/L, range 1–303 mg/L), 5 mg/L (IQR 2–12 mg/L) for those with cerebral infarction and 7 mg/L (IQR 2–24 mg/L) for those with myocardial infarction. The relation between CRP1 and age with trendlines is shown in figure 1. The Spearman correlation coefficient was – 0.072 (p = 0.032) and 0.146 (p = 0.003) among the cases and the controls, respectively. For bacteraemic patients the median CRP1 was 209.5 (IQR 110–320), 175 (IQR 83–271) and 176 mg/L (IQR 103–278), in the youngest, median and oldest age group, respectively. Corresponding results among the controls were 4 (IQR 2 – 11), 6 (IQR 2 – 20) and 11 mg/L (IQR 3 – 43).

For bacteraemic patients, the medians and IQRs of CRP1, CRP2 and CRP3 in the three age groups are shown in Figure 2. The youngest group had a significantly higher CRP1 level than the intermediate group (p = 0.003). For CRP2 both the difference between the youngest and the intermediate group (p = 0.04) and the difference between the youngest and the oldest group (p = 0.026), were statistically significant. There were no significant differences for CRP3.

The sensitivity of CRP in detection of bacteraemia according to age group, bacterial species and gender at different cut-off values is shown in table 1. At all cut-off points, the sensitivity is significantly better for S. pneumoniae than for E. coli, but we were not able to identify any differences in diagnostic sensitivity regarding age groups.

The ROC-curves for the different age groups are shown in figure 3. The AUCs are 0.968 (95% confidence interval (CI) 0.952–0.985), 0.940 (95% CI 0.922–0.958) and 0.923 (95% CI 0.888–0.958) for the age groups 16–64 years, 65–84 years, and ≥ 85 years, respectively. The AUC for the youngest age group was significantly greater than that for the intermediate as well as the oldest age group (z-test, p < 0.05 for both comparisons).

We were not able to confirm the hypothesis that the CRP-response in bacteraemia is age-dependent to any clinically important degree. There was a slight, though statistically significant negative correlation between age and initial CRP value as well as a higher area under the ROC curve for the youngest patients, but this did not translate into a clinically meaningful difference in sensitivity for any relevant cut-off value for CRP. The study may have been underpowered for a comparison of sensitivity, but when the age groups were collapsed into broader classes (results not shown), thus improving the power, the negative results regarding sensitivity persisted.

Accordingly, this study supports the use of CRP as an indicator of possible infection in the elderly with the same cut-off values as in younger adults. This result should, however, be interpreted with several reservations.

First, we cannot completely rule out selection bias, since we do not know if the blood cultures in some instances were drawn after the results of the CRP-tests were known, thus increasing the possibility that some cases of bacteraemia remained undiagnosed in cases with low CRP. Moreover, fever is a very common indication for having a blood culture drawn, but is less frequent in elderly patients with infection 18. Both factors could bias the results towards higher CRP levels in the elderly patients, and this trend may be strengthened by the fact that elderly patients more often have non-infectious comorbid conditions characterized by high CRP concentrations.

Second, we lack information on the duration of symptoms prior to CRP testing. A substantial proportion of the patients had their CRP1 drawn at admission. If there exists a systematically increased pre-hospital delay among the oldest, a slower CRP response in this group could be masked.

Third, we have insufficient clinical information as to include the potential confounding factors of comorbidity, disability or frailty upon the CRP response, an association that has been suggested by others 1920. Neither do we have sufficient information on the clinical severity of the infection.

It should be noted that our results are valid only for bacteraemia with E. coli or S. pneumoniae. Our study was not designed to assess the sensitivity of the CRP-response for severe bacterial infections that does not result in a positive blood culture for one of these bacteria. Thus, one should be careful in generalising our results to different clinical settings. Furthermore, the choice of control group can be criticized as both cerebral and coronary infarction may lead to elevated CRP. However, the choice was based on clinical grounds as these two conditions represent the main alternative diagnoses in the emergency room, especially when dealing with elderly patients.

The small relative difference between the age strata persisted at day 2–3, but disappeared at day 4–7 (Figure 2). This weighs against the hypothesis that the CRP response among the oldest is delayed, as in this instance we would have expected the progress from the first to the second assessment to differ according to age. It also weighs against the hypothesis of a prolonged inflammatory response in human old age 11, as is seen in aged mice 21. There may, however, have been a selection bias in the ordering of a second and a third measurement. We have no information on the reasons why these repeated measurements were ordered.

Thus, taking these important reservations into account, there is still a real possibility that there may exist a clinically relevant age related difference in CRP response in systemic infection, at least in invasive bacterial infections not causing a positive blood culture. What factors are in favour of this hypothesis?

In ageing research it is widely accepted that ageing is characterized by a systemic, low-grade inflammatory state 22. It is also acknowledged that this subclinical proinflammatory status, interacting with genetic background (evolutionary selection of proinflammatory genes beneficial in early age), may trigger the onset of frailty and age-associated diseases 222324. Innate immunity is viewed as being mainly well preserved, but immune changes seen in old age also affect innate immunity 24. Studies on possible age-related changes in proinflammatory cytokines (and thus the CRP response) in endotoxiemia have yielded diverging results 25262728. A recent study on gene expression in endotoxin-stimulated macrophages from young and old mice showed reduced expression of proinflammatory cytokines as well as Toll like receptor signalling pathways with increasing age 29. Another study showed that the gene expression of proinflammatory cytokines was significantly lower in aged mice than in young at 24 hours after stimulation with endotoxin, but higher at 72 hours 21. Thus, although still controversial, experimental studies do open up for a weaker proinflammatory response and thus a limited production of CRP.

There seems to be a convincing and clinically important difference in the sensitivity of CRP between patients infected with E. coli and S. pneumoniae. This finding accords well with the results of other studies. The CRP concentration is associated with mortality and organ failure 30, and it is well known that S. pneumonia consistently causes serious infections, while the range of severity is much broader for infections with E. coli. The finding of a gender difference in sensitivity in one particular age stratum, on the other hand, seems not biologically plausible, and we suspect this association to be spurious.

We conclude that there exists a statistically significant association between age and CRP in invasive bacterial infections. However, this association may not be of a magnitude that makes it clinically important for CRP as a diagnostic tool in bacterial infections associated with a positive blood culture. Further studies are needed to decide whether markers of the aging process such as comorbidity and frailty influence the diagnostic value of CRP as a marker of infection, as well as whether the diagnostic performance of CRP is affected by severity of infection.

This study was financed by Aker university hospital and by Ullevaal university hospital. The authors have no competing interests.

ALW participated in all parts of the study, both in the design of the study, data collection, statistical analysis and interpretation, and in the writing of the manuscript. KGB participated in performing the statistical analysis, the interpretation of the data and in the writing of the manuscript. TBW participated in the design of the study, the interpretation of the statistical analysis and in the writing of the manuscript, including revising it critically for important intellectual content.

All authors have read and approved the final manuscript.