BASEL AND ZURICH, SWITZERLAND--Calcitonin precursors, especially procalcitonin, may be reliable markers for sepsis in critically ill patients. In fact, they may be even more accurate than the established markers--C-reactive protein, lactate, and interleukin (IL)-6.

Those were the implications of two Swiss studies that involved a total of 506 critically ill patients. Their results represent further refinement in the diagnosis of sepsis, which has long been hampered by difficulty in differentiating systemic infection from noninfectious causes of the systemic inflammatory response syndrome (SIRS). "Since it is hard to tell who has an infection, at present almost everybody who comes to the intensive care unit (ICU) gets antibiotics," pointed out Beat Müller, MD, one of the lead investigators, in an interview with PULMONARY REVIEWS. Thus, diagnosing sepsis with procalcitonin may help to reduce this type of antibiotic overuse.

CALCITONIN PRECURSORS VS TRADITIONAL MARKERS

Dr. Müller headed up a prospective cohort study of 101 medical ICU patients (age, 23 to 86 years) with a broad range of illnesses, the most common of which were respiratory conditions, such as pneumonia and chronic obstructive pulmonary disease.[1] This population was unique in that it wasn't handpicked according to highly selective inclusion criteria.

"We purposely had a group of nonselected patients," said Dr. Müller, from the Department of Internal Medicine at the University Hospitals in Basel, Switzerland. "The intent was to study not just young patients, but polymorbid elderly patients as well."

The patients underwent blood tests for serum calcitonin precursors, C-reactive protein, IL-6, and lactate on the day of admission to the ICU, day 2, and the day of ICU discharge or death. They were assessed for clinical evidence of SIRS, sepsis, severe sepsis, or septic shock at admission and at the time of blood collection. The investigators were unaware of serum calcitonin precursor and IL-6 levels during the assessments.

SIRS was found in 99% of patients at admission, 96% on day 2, and 68% on the day of discharge or death. Sepsis or septic shock was diagnosed in 53% of patients at admission, 60% on day 2, and 36% on the day of discharge or death. Five percent of patients developed sepsis during their ICU stay.

In the absence of infection, serum calcitonin precursor concentrations were similar among patients with and without SIRS. However, these levels were significantly higher in patients with sepsis or septic shock than in aseptic patients with or without SIRS. In addition, calcitonin precursor levels were significantly higher in sepsis patients who died than in those who survived (33.5 ng/mL vs 17.4 ng/mL).

Calcitonin precursors were 89% sensitive and 94% specific for sepsis at a serum level above 1 ng/mL, making them significantly more accurate than the traditional markers. At 100 mg/L, for example, C-reactive protein was only 71% sensitive and 78% specific for sepsis.

PROCALCITONIN IDENTIFIES PATIENTS AT RISK

The calcitonin precursor procalcitonin was useful for detecting sepsis in a second Swiss study, a retrospective analysis of 405 trauma patients (mean age, about 40 years) by Guido A. Wanner, MD, and colleagues.[2] These patients had serial tests for plasma procalcitonin over a three-week period, starting within four hours of a blunt or penetrating trauma.

During the entire follow-up period, procalcitonin levels were significantly higher in the trauma patients than in a control group of 93 patients admitted for arthroscopy or elective removal of implants. The greatest increases occurred in trauma patients with an Injury Severity Score of 25 or higher.

Forty-five of the 339 trauma patients who survived for more than three days developed sepsis, which was linked to statistically significant increases in plasma procalcitonin levels. Sepsis patients had significantly higher levels of plasma procalcitonin than did patients with noninfectious SIRS. Furthermore, peak procalcitonin concentrations during the first three days after admission were a strong predictor of sepsis during the early and late posttraumatic course. Peak levels also predicted severe cases of SIRS and multiple organ dysfunction syndrome.

"THE" MARKER OF SEPSIS?

Despite the findings of these two studies, procalcitonin should not be the only marker physicians rely on to diagnose sepsis, according to Jean-Louis Vincent, MD, PhD, an intensivist at Erasme University Hospital in Brussels, Belgium. "Although procalcitonin is certainly a good marker of infection, it, like [C-reactive protein] and many others, is not the marker," he wrote in an editorial accompanying Dr. Müller's investigation.[3]

Indeed, procalcitonin was less sensitive and specific for sepsis than was C-reactive protein in another recent study.[4] Also, "raised procalcitonin levels have been reported in other conditions associated with an inflammatory response, including trauma, major surgery, cardiac surgery, and heat stroke, and are therefore not specific for infection," added Dr. Vincent. Procalcitonin, he suggested, may be most useful in combination with C-reactive protein to enhance the latter marker's accuracy.

Additional words of caution came from Bradley A. Boucher, PharmD, a Professor of Clinical Pharmacy at the University of Tennessee in Memphis. He suggested that procalcitonin may be more useful for monitoring than for diagnosis. "Its possible role as a monitoring tool is, in my mind, the bigger issue here," he told PULMONARY REVIEWS. "Serial procalcitonin measurements, for example, may help us determine when antibiotic therapy for sepsis has succeeded."

Unfortunately, data on procalcitonin in sepsis monitoring are scarce. However, "two modest studies have demonstrated a decrease in procalcitonin concentrations associated with the administration of antibiotic therapy," wrote Dr. Boucher in an editorial accompanying Dr. Wanner's study.[5] He likewise does not see procalcitonin as the marker for sepsis but as one of many potentially useful markers. "In fact, if it doesn't show a significant improvement in accuracy as we learn more about it, it might just end up as more of a laboratory curiosity than a clinical tool," he concluded.

--Timothy Begany

References
1. Müller B, Becker KL, Schächinger H, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28:977-983.
2. Wanner GA, Keel M, Steckholzer U, et al. Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients. Crit Care Med. 2000;28:950-957.
3. Vincent J-L. Procalcitonin: THE marker of sepsis? Crit Care Med. 2000;28:1226-1227.
4. Ugarte H, Silva E, Mercan D, et al. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med. 1999;27:498-504.
5. Boucher BA. Procalcitonin: clinical tool or laboratory curiosity? Crit Care Med. 2000;28:1224-1225.

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