Procalcitonin (PCT) is a blood biomarker whose concentrations rise in response to systemic inflammation caused by bacterial infection and sepsis. In recent years, the Food and Drug Administration (FDA) has approved new PCT assays and expanded indications for PCT tests that allow healthcare providers to use this biomarker as both an antimicrobial stewardship tool and to predict 28-day mortality in sepsis patients.
But PCT has limitations, the assays for it can be expensive to run, and studies on its efficacy in specific age groups, including pediatric and neonatal patients, have produced mixed results. In light of the rapid adoption and expansion of PCT testing in healthcare—fueled by those FDA approvals and the COVID-19 pandemic—AACC recently issued new guidance for both clinicians and laboratory professionals on how best to use PCT tests.
While there has been an avalanche of studies proving PCT’s effectiveness in the realms of antimicrobial stewardship and sepsis, “there wasn’t really a good, comprehensive review from a laboratory-based body, where we could rigorously look at the studies but also limitations of the lab test itself to make recommendations as a whole on how to use this test,” said Alison Woodworth, PhD, DABCC, FADLM, clinical director of global laboratory services at CTI Clinical Trial & Consulting Services, and an author of the guidance.
That is, until now.
THE CHALLENGES OF PCT TESTING
Despite their global popularity, PCT tests are still relatively new in the U.S., with FDA only starting to approve them for antibiotic stewardship in 2017.
“These tests have been used for many years in Europe, but they weren’t available in the U.S.—particularly as FDA-approved or FDA-cleared assays—on the routine analyzers that most of us have in clinical laboratories,” said Allison Chambliss, PhD, DABCC, FADLM, associate clinical professor of pathology and laboratory medicine at the University of California Los Angeles David Geffen School of Medicine, and an author of the guidance.
Interpreting results, especially deciphering what they mean in relation to both sepsis mortality risk and antibiotic stewardship, is not straightforward either, especially for nonlaboratorians. Because of this, Chambliss said, “we thought it was important to pull the literature together, especially clinical trials that had been done in Europe to support the FDA approval and bring PCT over to the U.S.”
Another challenge of testing for PCT is that it’s “fairly expensive,” said Angela Fung, PhD, FCACB, clinical assistant professor at the University of British Columbia and clinical chemist at St. Paul’s Hospital, and reimbursement is not always guaranteed. “Despite the published trials, the effectiveness of PCT in real-world implementation requires collaboration and practical considerations such as developing testing protocols (i.e., who is tested and how frequently); interpretation guidance (e.g., determining different cut offs); and test utilization strategies to determine when to approve or cancel tests and which also have to include education,” she said.
At the start of the COVID-19 pandemic, when clinicians and laboratorians were desperately trying to find any test or treatment that could help care for patients who were sick with the virus, PCT tests were also thrown into the fray for patients who had tested positive for SARS-CoV-2, Fung said.
The newness of PCT assays, combined with their use during COVID-19, has led to them being ordered in situations where they may not be appropriate. “A lot of residents started to order PCT based on different hospital practices,” she said. “We spend a lot of effort educating about appropriate test utilization.”
RECOMMENDATIONS FOR USE IN ADULTS AND CHILDREN
While clinical trials on PCT testing done in Europe have been helpful in establishing its effectiveness in sepsis guidance and antibiotic stewardship, there are limitations in what those results can tell healthcare providers and laboratorians in another country. Most of the trials were done with one particular test, and on adults. “Anybody who wanted to use PCT, that’s all they had to go off of,” Chambliss said, even though there are differences in available PCT assays and what their results mean. “Using the same test in the same lab and watching the value either rise or fall using the same test—that is much more powerful than using a single cutoff from these trials as a guide to management,” she added.
One of the benefits of the new AACC guidance is that it distinguishes between different clinical indications of use, she said. “Are you looking to diagnose the patient? Looking to determine when to start antibiotics or, more importantly, when to stop antibiotics? The cutoffs are different,” Chambliss said.
PCT testing is also not as well studied in children, which is why the AACC guidance includes a special section on its use in pediatrics and neonates. While PCT assays have been used to test for severe bacterial infections in children—including bacterial meningitis, urinary tract infections, sepsis, and bacteremia—the utility and accuracy of these tests have not been as closely evaluated in children as in adults.
Plus, PCT cutoffs in adults don’t always mean the same thing in children, especially newborns, as PCT is high for the first 48–72 hours of a baby’s life. “If you’re measuring PCT in a baby who doesn’t actually have a bacterial infection, but you’re using reference ranges and rules that were established in adults, you might misinterpret that result as elevated,” Chambliss said. That can lead to unwarranted and potentially harmful treatment.
While studies have been done on PCT levels in children, the authors of the AACC guidance didn’t feel that these studies were large enough to determine standard levels that can be applied across different pediatric patient populations.
“We stress in the document that it’s important to either establish pediatric intervals or at least acknowledge these limitations with interpretative information to ensure that clinicians are not misinterpreting elevated PCT in those age groups,” Chambliss said.
It’s also worth noting that, although COVID played a role in the surging popularity of PCT assays in practice, the team that wrote AACC’s guidance did not include that as part of the guidance, as PCT is considered a marker for bacterial, not viral infections. Instead, the guidance authors focused on respiratory diseases in which PCT has been more widely studied, including bacterial pneumonia.
PARTNERING WITH PROVIDERS TO IMPLEMENT THIS GUIDANCE
Making sure that PCT assays are used for the right patients and interpreted in the right way can be challenging, especially since the assays are new, evolving, and might have been overused during COVID. This guidance should help, its authors say.
“One of the biggest issues in implementing these tests is that people will just implement them and not do it correctly,” said Woodworth. “There can be a big misunderstanding about what the results mean.” That’s especially true if clinicians are ordering PCT assays without the laboratory’s input or without asking clinical laboratorians for help interpreting the results, since many factors and conditions can lead to PCT levels being different from one patient to another. For example, someone with a chronic illness may have an elevated inflammatory response and a higher PCT baseline than other patients. PCT also can spike due to surgery or giving birth, and may not be an indication of a bacterial infection right after those events.
“It really isn’t a single measurement but a monitoring over time,” said Woodworth. “We really want to help laboratories and also clinicians set up programs to establish when to measure PCT, how frequently they should measure it in what patients, and then also provide them with cutoffs in terms of concentrated PCT in the bloodstream that might predict severe disease or the need to change treatment.”
That’s why the AACC guidance also includes a section on how PCT testing should be incorporated into broader antimicrobial stewardship efforts. “The laboratory and these antibiotic stewardship clinicians, infectious disease clinicians, and pharmacists should work together so that we can present laboratory data in a way that supports the optimal use of these tests and optimal use of antibiotics,” Chambliss said.
As laboratories implement PCT assays and add this biomarker to their test menus, “it’s really important to determine how the results are going to be displayed and what kinds of interpretative comments go with the test results,” she said. “Hospitals and laboratories should develop interpretative algorithms, and many have.”
As a healthcare system introduces a PCT assay as a testing option, “rather than just validating the test and opening it up for ordering, we should make sure we’re providing effective interpretative information and that we’re involving appropriate stakeholders so that information will be seen and followed,” Chambliss added.
As an example, at St. Paul’s Hospital in Vancouver, British Columbia, PCT tests are strictly used for ICU patients suspected of having bacterial infection and for the purpose of antibiotic stewardship only. “There’s a protocol in place for daily rounding with the infection control and antibiotic stewardship teams to look at the PCT result and look at the clinical picture together” in order to determine antibiotic therapy discontinuation, Fung said. That and cancelling tests for unapproved clinical indications and situations goes a long way in making sure PCT assays are used and interpreted in the right situations and in the right ways.
Jen A. Miller is a freelance journalist who lives in Audubon, New Jersey. +Twitter: @byJenAMiller