Over a century ago, it was observed that “…the result of a laboratory test should have, in a given case, the same value as a cardinal symptom or an approved clinical sign….many … forget this, and fail to correlate the laboratory findings with the clinical findings.”(39
) We also observed that used alone, procalcitonin performed similarly to existing clinical prediction rules, but that indiscriminately adding procalcitonin to all patients, regardless of clinical risk category, provided little additional information. However, clinical prediction rules have two important limitations – physicians may misapply or not remember them, and within a given risk category there can be a significant range in outcome. We therefore sought to determine if procalcitonin could address these concerns, first as a stand-alone test, and then layered on top of clinical risk assessment.
Our main finding was that in a large, contemporaneous cohort of patients diagnosed in the ED with CAP, patients with a procalcitonin < 0.1 ng/ml had a low 30-day mortality rate, even in patients defined as high-risk by established clinical risk prediction rules. Thus, adding procalcitonin to the assessment of high clinical risk patients significantly improved the ability to rule out the likelihood of death. There are, however, important caveats to these observations.
First, although a procalcitonin < 0.1 ng/ml in high-risk subjects had a very low LR for death, the relatively wide 95% confidence interval merits caution. Second, a good outcome for a high-risk subject could either be because the risk prediction tool was inadequately discriminant or because the ensuing care averted an adverse outcome. Thus, a retrospective identification of a rule or test with potentially valuable test characteristics should be followed up by prospective assessment of its impact on clinical decision-making and outcomes. The potential of the PSI was not fully understood until Marrie et al and Yealy et al demonstrated that it could help physicians safely withhold hospital admission and intravenous antibiotics.(37
) We similarly recommend that procalcitonin as an adjunct to clinical tools be tested prospectively before wider use.
Our primary goal was to determine how procalcitonin might enhance existing CAP prediction rules and decision making. We recognize though that physicians often do not explicitly calculate PSI in daily clinical practice. However, the same factors that comprise PSI and other prediction rules also go into the bedside clinical judgment many physicians use to guide their decisions. Our results therefore suggest that procalcitonin may aid decision making in high risk patients, defined explicitly or implicitly with the PSI or a similar tool. Most importantly, we again emphasize that procalcitonin should never be used in isolation to make clinical decisions, and does not replace physician assessment.
Current CAP guidelines recommend that clinically high risk patients be hospitalized, and that ICU admission be considered for patients in the highest risk categories. (7
) Of interest, Marrie et al also observed that many clinical high-risk patients might be safely managed at home.(43
) Our data suggest that procalcitonin may aid in identifying PSI/CURB 65 high risk patients who will rarely suffer mortal and other complications. Thus, there could be considerable benefits, both in terms of conserved resources and antibiotic management, if one could better stratify high risk patients. Prospective studies are needed to determine if procalcitonin can improve physician management decisions and outcomes in high risk patients.
However, two clinically important questions merit emphasis. First, is a low procalcitonin in a high risk patient clinically obvious, and only a “costly surrogate measure of health status”? (44
) We believe not, since these patients did not appear different than other high risk patients across a wide range of baseline variables, suggesting that a low procalcitonin is not particularly obvious at the bedside. Second, why did those patients with high clinical risk scores, yet low procalcitonin levels, do so well? We found that a low procalcitonin was associated with shorter length of stay, lower proportions of mechanical ventilation and ICU admission, and a more benign severe sepsis phenotype. This suggests that while CAP patients with high clinical risk scores often already have severe sepsis at ED presentation or develop it later, that a low procalcitonin portends a less severe course, potentially explaining the associated low mortality.
Of note, our observational study design does not allow us to address whether procalcitonin can be useful in guiding antibiotic treatment, based on ability to determine bacterial infection. Instead, our work focused on procalcitonin and links to adverse outcomes in those already diagnosed with CAP. We recognize however that these two domains, while theoretically distinct, are practically intermingled. For example, patients with CAP that have positive blood cultures tend to fare worse, and low procalcitonin is associated with both low positive culture rates and low mortality.
We conclude that in a large, multicenter CAP cohort, patients in the lowest procalcitonin tier (≤ 0.1 ng/ml) were at a low risk of death, regardless of clinical risk. Used indiscriminately, procalcitonin provided little additional information over PSI and CURB-65 risk assessment. However, a selective two-tiered approach of first performing a clinical risk assessment, and then obtaining procalcitonin only in those judged to be high-risk, offers potentially important value.