American Association for Clinical Chemistry
Better health through laboratory medicine
February 24, 2005
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In This Issue . . .

Searching for that Magic Bullet: Is Procalcitonin the Key Sepsis Biomarker?
The release of a new assay brings procalcitonin to the forefront in the quest to beat sepsis through early diagnosis.


Searching for that Magic Bullet: Is Procalcitonin the Key Sepsis Biomarker?

Severe sepsis afflicts an estimated 750,000 patients each year in the United States, a rate expected to rise to one million cases a year by 2010, according to the Society of Critical Care Medicine. Early treatment is vital to stopping the spread of infection, making early diagnosis methods a top research priority. Appropriate treatment is also important; clinicians don’t want to waste valuable time or money administering antibiotics that the patient is not responding to because of resistance or because it’s the wrong treatment for the infection. Over the past decade research efforts to improve diagnosis have focused on identifying a “magic bullet” biomarker, which provides high sensitivity and specificity to give clinicians a snapshot of a patient’s septic state. In recent years, procalcitonin (PCT) has emerged as a potential contender to become this biomarker, but some researchers insist that any decision on its value as a septic diagnostic component is premature. However, PCT’s prognostic value recently got a boost from the FDA, when the agency cleared the Brahms PCT-LIA assay to aid in the clinical assessment of critically ill patients for severe sepsis and septic shock. This month, Strategies looks at the impact this assay will have on sepsis diagnosis and the questions still surrounding PCT as a sepsis biomarker.

When a patient’s immune system fails to mount a balanced response to a septic infection, a cascade of events including widespread inflammation and blood clotting can follow at an alarming rate. The rapid course of these insufficient or excessive reactions, known as severe sepsis or septic shock, demands a rapid diagnostic tool that can indicate infection, as well as its behavior, in order for physicians to administer appropriate antibiotics to combat the infection.

Diagnosing sepsis and septic shock have traditionally been based on clinical parameters such as white blood cell counts, temperature, respiratory rate, and heart rate, explained Scott Hanes, PharmD, a clinical associate professor of pharmacy at the University of Illinois, Chicago. “However, none of those variables really have any prognostic value, which is why people have been searching for indicators such as procalcitonin that may have some prognostic value.” For instance, it’s hard to tell a patient’s mortality risk from septic shock based on their temperature; having a temperature of 102 versus 102.5 doesn’t reveal much about their inflammatory levels.

Research indicates that PCT has more prognostic value over other biomarkers, such as C-reactive protein (CRP), because it is more specific for infection, said Hanes. In addition, PCT is a more likely “magic bullet” candidate because levels tend to rise soon—within 6-9 hours—after an infection develops and systemic consequences ensue, thus allowing clinicians to assess whether the patient is going into severe sepsis. CRP levels take longer to rise in adult patients, often too long in order to reverse the outcome, said Hanes.

The clinical parameters, such as blood count and temperature, are measured using cultures from blood, urine, cerebrospinal fluid, or bronchial fluid. Unfortunately, these culture-based assays often take 24 or 48 hours to grow. Until recently, PCT assays were only available in Europe. But in January, the BRAHMS PCT-LIA, produced by BRAHMS Ag (Berlin, Germany) was cleared by the FDA for clinical use in the U.S., although it still only available for research use in Canada. While the PCT-LIA is a manual assay that uses a luminometer, Brahms also makes a semi-quantitative, rapid version of the assay—PCT Q—which is currently available for research purposes in the U.S., but will be submitted to the FDA for review this year. The PCT-Q produces results in 30 minutes.

The PCT-LIA assay is estimated to produce results in two hours, but even that might not be rapid enough to identify some cases of sepsis, said Shawn Carrigan, a PhD student at McGill University’s Biomedical Engineering Department, and co-author of an August 2004 review article on the challenges of sepsis diagnosis in Clinical Chemistry. PCT and the related inflammatory biomarkers that researchers are tracking can fluctuate over periods of hours with the onset of sepsis, so the value can change significantly from the time you take the sample until the assay produces results, even if its only three hours. “If you are looking at something which cycles over a period of a couple hours, it’s kind of pointless to run an assay that takes longer than the cycle period,” Carrigan explained.

An Opportunity to Direct Therapy

The true prognostic value of PCT as a sepsis mark and an assay like the PCT-LIA, could be in its ability to guide treatment. “A lot of times, we don’t know what we are treating,” said Hanes. “If you don’t know what you are treating, but you know you have an infection, you might be able to use this as a marker of whether or not you are curing the infection, even though you don’t necessarily have the “bug” to monitor.” In addition, measuring PCT levels could help determine when to stop antibiotic therapy, particularly if the antibiotic used turns out to be the wrong one.

“I think you are really looking at a paradigm shift in the diagnostics,” said Carrigan. “If you can do three assays in an hour and get three different data points, it makes it much more rapid for a clinician to say, ‘Well, this antibiotic isn’t working, we need to try something else.’”

While Carrigan agrees that PCT appears to be the most promising biomarker at this time, he doesn’t believe it is bullet-proof. “The problem is that a lot of people are looking for the easy solution and that means one marker, but this fails to account for the patient-to-patient variability,” he said. “I think you’d be better off monitoring a panel of markers and seeing what happens. For instance, if procalcitonin doesn’t change, but one of the other inflammatory markers skyrockets, then maybe there’s a problem. When you start monitoring these things in a real-time basis, I think it’s going to take people a fair amount of time to get used to interpreting the data and responding to it.”

For more information:
  • BRAHMS PCT Assays: Information on the recently FDA-cleared PCT-LIA assay is available at www.procalcitonin.com.
  • Toward Resolving the Challenges of Sepsis Diagnosis: The August 2004 Clinical Chemistry review of past and present diagnostic methods, as well as suggested revisions of current diagnostic paradigms, written by Shawn D. Carrigan, et. al., of McGill University’s Biomedical Engineering Department: http://www.clinchem.org/cgi/content/abstract/50/8/1301