Procalcitonin passes automation hurdle

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Anne Paxton

December 2016—Matt Damon in Interstellar. Julia Roberts in The Player. Gene Hackman in Young Frankenstein. When movie stars appear in uncredited parts, it’s usually for a cameo, not a leading role. But in diagnostics, an uncredited or off-label use of an assay might be its main use—possibly even its most clinically important use.

Procalcitonin should be viewed as a complementary test, not as a competitor to testing of lactate, Dr. Stefan Riedel says. “Both laboratory tests are important for the diagnosis and management of patients with symptoms suggestive of sepsis.”

Such is the case with the sepsis biomarker procalcitonin (PCT). It’s not a new biomarker; clinicians in Europe have ordered it for the past two decades and in the U.S. for at least seven years. PCT assays, developed by German biotechnology company Brahms and later licensed to Thermo Fisher Scientific, as well as the Vidas enzyme-linked fluorescent immunoassay developed by BioMérieux, have been approved by the Food and Drug Administration since 2008 to assess the mortality risk of patients with suspected sepsis.

Last March, the FDA expanded the clinical claims that PCT diagnostics manufacturers can make to include a comparison of PCT measures over four days after admission as a gauge of the patient’s response to therapy. But PCT’s official FDA-approved uses are still only one facet of the assay’s actual role in addressing sepsis.

By many accounts, it is procalcitonin’s unadvertised, unofficial applications, more than the approved uses, that have been drawing clinicians in many hospitals to order the assay in increasing numbers. Study after study shows that PCT—when results can be obtained speedily—is a highly effective biomarker for the differential diagnosis and for managing antibiotic treatment as well.

Given this background—even though automated PCT assays were already available in the U.S. on the Brahms Kryptor and BioMérieux Vidas platforms—the FDA’s decision in June to approve an automated PCT Brahms assay for Roche Diagnostics’ Elecsys platform could significantly expand clinicians’ use of PCT. Requiring no reagent preparation or hands-on testing, the new test could make quick results more widely available, increasing the practicality of PCT’s off-label applications and reinforcing PCT’s increasingly central role in ameliorating sepsis

“The literature coming from colleagues, especially those in Europe, makes it pretty clear that PCT has value in the management of sepsis,” says Joshua A. Hayden, PhD, assistant director of the central laboratory at New York-Presbyterian Hospital–Cornell Campus. “And now, with the FDA approval of Roche’s test, making this analyte available on a random-access platform which many labs are going to have already, there is a real opportunity to start offering this testing to clinicians without undue operational burdens on the laboratory.”

In interviews with CAP TODAY, pathologists and clinicians who have extensive experience with PCT explain how it has become so pivotal a test and why this new choice in automated platforms could be a milestone for managing sepsis.

The FDA drew attention to sepsis diagnostics on June 23 when, based on findings of the U.S. Multicenter Procalcitonin Monitoring Sepsis Study (MOSES), a trial designed by Thermo Fisher Scientific, the agency authorized marketing of both Roche Diagnostics’ and BioMérieux’s Brahms PCT test, following a three-month review. (According to Roche and Thermo Fisher, the MOSES trial design leveraged the same patient samples to enable a “universal analysis” approach to demonstrate substantial equivalence to the FDA, resulting in the clearance of the Elecsys Brahms PCT assay.)

Changing regulatory requirements have also intensified hospitals’ concern about best approaches to suspected sepsis. Beginning with October 2015 discharges, the Centers for Medicare and Medicaid Services adopted a Severe Sepsis and Septic Shock Management Bundle of measures for hospitals to follow for fiscal year 2017 payment determination, including measures hospitals must take within three hours of admission of a suspected sepsis case.

Dr. Newton

“We’re all having to meet those standards or metrics,” says James Newton, MD, infectious disease specialist and antibiotic stewardship director at Washington Regional Medical Center, Fayetteville, Ark. But every institution handles treatment somewhat differently. At his hospital, clinicians aim to administer a large fluid bolus of 30 mL/kg plus levofloxacin, vancomycin, and meropenem within the first hour, providing a broad spectrum of coverage. Then there’s an effort to narrow the spectrum with laboratory tests. But traditional lactate is inadequate to help with the narrowing. “If you see someone with a lot of vague symptoms and check their lactate, it can be elevated for lots of reasons,” Dr. Newton notes.

With a one-hour turnaround, this is where a PCT assay can begin to help with a diagnosis. Studies including a meta-analysis of 30 earlier trials have found that PCT can differentiate effectively between true sepsis and systemic inflammatory response syndrome of noninfectious origin (Wacker C, et al. Lancet Infect Dis. 2013;13[5]:426–435).

PCT levels can also help predict whether the patient is responding to antimicrobial therapy, Dr. Newton explains. With most bacterial infections, unlike viral or parasitic infections, a handful of proinflammatory cytokines are released and raise PCT levels. If an antibiotic is killing bacteria, the patient’s PCT levels will fall in accordance with the protein’s defined half-life. If PCT starts at 100 and is still at 80 in 24 hours (rather than 50), “that tells me it’s time to make a change in the antibiotic regimen.”

Washington Regional is evaluating whether switching from the Brahms/BioMérieux platform to the Elecsys Brahms PCT test will be helpful. “We’re doing a month-long test with the Roche product, running both platforms in parallel on specimens, and it’s up to the laboratory director to decide whether we want to switch. I’m looking for whether it will give me the same information we’re used to getting.” With turnaround time now at one hour, “if we get it down in half that time, it helps for sepsis, but for the everyday routine follow-up that we use PCT for, it’s not going to make a difference whether we get a rapid return or not. We’re just looking for the pattern.”

PCT levels have their quirks. “In the first two days of life, PCT is usually high, and people who have had severe trauma, including major surgery, have high levels, sometimes transiently,” Dr. Newton says. In some thyroid cancers, PCT is also high. There are sometimes conflicting data in the literature relating to other symptoms, Dr. Newton notes. PCT is reliable for diagnosing septic arthritis and meningitis, but it’s clearly not a good test for things like cystitis and cellulitis, which are common infections but don’t produce high PCT levels. “We don’t know why. It’s one of those things that comes with experience of using the test and treating patients,” he adds.

“We’re trying to use our database to look at all these patients and disease processes, and look for both positive and negative predictive value. With a particular symptom complex, is the negative predictive value of PCT high enough where I could honestly say I don’t need antibiotics for this patient? Is the PCT test accurate enough to identify a cystitis versus a pyelonephritis?”

Those questions remain to be answered, and Dr. Newton thinks it’s too early to say whether the Roche platform will expand the use of PCT. “It will allow people to get experience with the test, because if it’s part of an automated platform, then it will end up like tests for calcium or magnesium—things you’d like to see but don’t necessarily use every day. PCT is probably going to be thrown in that category at first.”