Procalcitonin do's and don'ts

Procalcitonin has become a hot topic in hospital medicine since 2017, when the FDA cleared use of the assay to help with antibiotic decision making in certain patients in the hospital.

The test has been the subject of formal clinical debates, like one held last year at Emory University, as well as a 2021 Annals for Hospitalists paper and not one but two Annals on Call podcasts in 2022.

It also comes up regularly in conversation among clinicians, said hospitalist Valerie Vaughn, MD, MSc, FACP, an assistant professor of medicine at the University of Utah School of Medicine in Salt Lake City. “I was just talking with a whole bunch of people about this … and what I argue is that the data are mixed on whether you should use it or not,” she said. “But what I know is true is that people are using it.”

On the rise

A recent analysis of hospital data across the state of Michigan showed growing use of procalcitonin, said Dr. Vaughn, who works closely with the Michigan Hospital Medicine Safety Consortium. “In the past year, use of procalcitonin has just ballooned, so about 20% of hospitalized patients now receive procalcitonin testing,” she said.

That's with wide variation across hospitals. “Some hospitals don't have it, so we see some hospitals where it's 0% of patients and others where it's almost 100% of patients,” said Dr. Vaughn.

COVID-19 likely increased the use of procalcitonin, which clinicians use to decide whether patients with the infection need antibiotics, said Dr. Vaughn. “Bacterial infections are relatively uncommon in COVID,” she noted. “But when they do occur, outcomes are really bad, so people are trying to identify, ‘Well, we shouldn't be giving everyone antibiotics, but who needs them?’”

Procalcitonin has a very good negative predictive value for bacterial co-infection (98.3% for a level of ≤0.1 ng/mL), according to a 2020 study led by Dr. Vaughn and published in Clinical Infectious Diseases. “We didn't find, actually, that its positive predictive value is very good, because it can be elevated for many other reasons,” she said.

Those other causes of elevated procalcitonin include renal failure, fungal infections, and parasites like malaria—all conditions that may affect hospitalized patients, said Gavin H. Harris, MD, an assistant professor of medicine at Emory, who presented the con side of the school's debate on the subject.

“Nonbacterial cytokine activation can increase procalcitonin at baseline … so we really have to be aware of confounders in which procalcitonin can be present. If we don't have baselines, this can be very problematic,” he said.

However, the reassurance provided by a negative procalcitonin has been particularly helpful during the pandemic, argued Joel Zivot, MD, an associate professor of anesthesiology and surgery at Emory who presented the pro side of the debate.

“When COVID first came and we saw these patients, we didn't really know what we were dealing with, and all of them got antibiotics,” he said. “So the fact that we were able to comfortably stop giving antibiotics to everybody automatically, that was I think a big breakthrough.”

No matter which camp you fall into, experts on both sides agreed there are do's and don'ts of ordering procalcitonin.

Where it's useful

The test's FDA-approved uses are to help determine if antibiotics should be started or stopped in patients with lower respiratory tract infections, such as community-acquired pneumonia (CAP), and if they should be stopped in patients with sepsis. High procalcitonin levels suggest a bacterial infection, whereas low levels suggest a viral infection or noninfectious cause.

“The procalcitonin is useful to determine if antibiotics are needed at all: The patient has a fever and is coughing. The procal is normal. Stop antibiotics,” said Brad Spellberg, MD, FACP, chief medical officer at the Los Angeles General Medical Center. “It is a useful psychological tool to help doctors be reassured that patients will do fine if their antibiotics are stopped.”

More than 20 randomized controlled trials, which have been meta-analyzed twice, have shown that incorporation of the procalcitonin result is associated with use of 25% fewer antibiotics and an overall mortality benefit, he added.

Although procalcitonin testing could reduce inappropriate antibiotic use, in practice, it can be difficult to change clinician behavior, said Nicholas Gowen, MD, FACP, an academic hospitalist, assistant professor of medicine, and associate program director of the internal medicine residency at the University of Arkansas for Medical Sciences in Little Rock.

“The residents and staff I see using it often just disregard it any time it doesn't agree with the antibiotics plan they have,” he said.

The problem is that giving antibiotics to a sick patient can be an emotional decision for many clinicians, according to Dr. Gowen. “We're always vaguely afraid that an individual patient will have a bad outcome because we failed to give antibiotics, so another data point that says there probably isn't a bacterial infection isn't often enough to sway most clinicians, particularly those who are having to move quickly,” he said.

In response to the fear that compels physicians to overuse antibiotics, an antibiotic stewardship program can help in encouraging proper use of procalcitonin, Dr. Spellberg said. “Like all tests, it must be stewarded. … The antibiotic stewardship team needs to reinforce the ability of the test to prognostically determine that patients will be safe with antibiotics being stopped,” he said.

This behavioral issue arose in the Procalcitonin Antibiotic Consensus Trial (ProACT), published in 2018 by the New England Journal of Medicine. Randomizing clinicians at 14 hospitals to receive procalcitonin results for their patients with suspected lower respiratory tract infection along with an antibiotic prescribing guideline didn't result in fewer antibiotics by day 30 compared to controls.

One potential reason for the negative findings, which conflicted with those of prior trials, was lower guideline adherence (65%), said lead author David T. Huang, MD, MPH, a professor of critical care medicine, emergency medicine, and clinical and translational science at the University of Pittsburgh who reflected on the findings in a 2020 Critical Care Clinics review article. “Although ProACT was designed to emulate real-world clinical practice, a main criticism of the trial was that its overall null result was due to clinician nonadherence,” he said.

Dr. Vaughn's use of procalcitonin followed the “slope of enlightenment,” she said. It begins with fervor among early adopters for a new technology and suddenly drops off in disillusionment before plateauing somewhere in between.

“When it first came out, every patient had a procalcitonin,” she said. “Then I was like, ‘This test is useless' because I was using it incorrectly, and then I stopped using it. And now I've kind of settled on this middle ground.”

For her, that means not ordering procalcitonin tests in patients who will receive antibiotic treatment regardless of the results. “If I think a patient has bacterial pneumonia, procalcitonin isn't going to tell me any new information, except maybe some risk stratification. But for the most part, you get that from their vital signs and their comorbidities,” said Dr. Vaughn, who is also the director of hospital medicine research and codirector of the Utah Quality Advancement Laboratory at the University of Utah.

She likes using the test when she's unsure if antibiotics are needed, like in a patient with COVID-19 and high fevers, or in situations where diagnostic tests aren't all aligning, such as in a patient with obesity presenting with suspected heart failure but a normal B-type natriuretic peptide level. “A negative procalcitonin could help push me in the direction of saying, ‘OK, let's treat this as heart failure first and see if they respond,’” Dr. Vaughn said.

Procalcitonin hasn't been tested in studies for its value in diagnostic uncertainty, Dr. Vaughn noted, but she sees benefits. “Let's say you have a patient come in, and they have respiratory symptoms and maybe an abnormal chest X-ray, but you're not sure: Is this a multifocal pneumonia or is it heart failure? Is it a COPD [chronic obstructive pulmonary disease] exacerbation? And if so, is it a COPD exacerbation from a bacterial infection?” she said. “[That's] the way I see people using it and the way I think it's best used.”

The ideal use of procalcitonin is when a patient is admitted with a likely viral diagnosis, such as confirmed influenza, but the hospitalist is worried about a secondary bacterial infection, Dr. Gowen said. “A negative procalcitonin in that situation could help the clinician avoid unnecessary antibiotics,” he said, adding that it can also be modestly helpful when viral and bacterial infection are the top two differential diagnoses.

Where it's not useful

There is also some agreement on when not to use the test in patients with infections. “In general, there's not a lot of good use for procalcitonin in patients with pneumonia,” said Joanna M. Bonsall, MD, PhD, FACP, during her talk at the Society of Hospital Medicine's CONVERGE conference earlier this year.

First, procalcitonin is not great for determining a pneumonia diagnosis, she said. This is a better job for point-of-care ultrasound (POCUS), which has greater than 90% sensitivity and specificity for diagnosing lung pathologies, said Dr. Bonsall, who is an associate professor of medicine at Emory and the chief of hospital medicine at Grady Memorial Hospital in Atlanta.

“If you don't have POCUS at your institution, the gold standard is actually a CT scan,” she said. “Both of these will provide you more information about pathologies than procalcitonin will.”

Second, procalcitonin is limited in its ability to distinguish bacterial from viral pneumonia. A meta-analysis of 12 studies in 2,408 patients with CAP found that a serum procalcitonin cutoff of 0.5 µg/L had a sensitivity and specificity for bacterial infection of 55% and 76%, respectively, according to results published in 2020 by Clinical Infectious Diseases.

“This is not reassuring for me to say definitively that my patient does or does not have bacterial pneumonia,” Dr. Bonsall said. “Now, if you're concerned about it, you can go back to cultures. But clinical judgment is better than procalcitonin.”

Dr. Spellberg added that procalcitonin is not a diagnostic test and thus is not intended to diagnose bacterial versus viral pneumonia. “It's a prognostic biomarker—it tells the doctor when it is safe to stop antibiotics,” he said.

In terms of stopping antibiotics, Dr. Bonsall noted that there have been no studies to date showing that procalcitonin can be used to reduce the duration of pneumonia antibiotics to less than that recommended by current guidelines. In their joint 2019 clinical practice guideline on CAP, the American Thoracic Society and the Infectious Diseases Society of America strongly recommend that antibiotic therapy be continued until the patient achieves stability and for at least five days.

Since subsequent trials have suggested that three days of antibiotics are sufficient for most patients with CAP, some hospitals, including Dr. Vaughn's, are moving toward three-day courses for certain patients. “All of the strongest evidence for procalcitonin is when to stop antibiotics,” she said. “But if you're already stopping antibiotics at three or five days, using procalcitonin isn't really that helpful in reducing duration.”

Dr. Gowen agreed. “With the modern ‘shorter is better’ movement championed by Dr. Spellberg, the antibiotic courses are often short enough that procalcitonin wouldn't make much difference,” he said, adding that it would be reasonable to use a drop in serial procalcitonins to de-escalate or stop antibiotics.

Even though the “shorter is better” philosophy is becoming more prevalent nationally, a procalcitonin level can still be useful when the hospitalist is on the fence about whether antibiotics are needed, Dr. Spellberg said. “I have used it many times to help convince teams that they can stop the ceftriaxone plus macrolide entirely on day 1 because the procal was not elevated,” he said.

Procalcitonin's overall effectiveness is probably greatest when deployed within a broader antibiotic stewardship program, particularly one extending into the postdischarge period, said Dr. Huang. In a new simulation analysis, published in January in BMC Infectious Diseases, his group found that high adherence (84%) would have been necessary to see a significant reduction in antibiotic use in ProACT.

“However, we also found that continued guideline adherence after discharge could potentially offer an opportunity for antibiotic reduction, as only a 76% rate of continued adherence would have resulted in lower antibiotic use,” said lead author Brian E. Malley, MD, MS, an instructor and research fellow in critical care medicine at the University of Pittsburgh.

Full guideline adherence in the hospital would have resulted in only about one fewer antibiotic day, the simulation found, but that decline nearly doubled with continued adherence after discharge, said Dr. Malley, who is also an emergency medicine attending. “The maximum effect of increased postdischarge adherence was 1.7 fewer days, so increasing postdischarge continued adherence may be a more impactful area to focus on in the future,” he said.

The general rule, as with any test, is not to order a procalcitonin unless the results are going to affect your decision making, especially since it can be expensive, Dr. Vaughn advised. “If it's going to impact your care, order it. But if you're going to give antibiotics no matter what the procalcitonin says, then don't get a procalcitonin,” she said.