PCT has shown to be a valuable biomarker for diagnosis and monitoring of clinically relevant bacterial infections, including:

• lower respiratory tract infections (LRTIs) 
• secondary bacterial infections in COVID-19 pneumonia 
• suspected sepsis 
• surgical site infections 
• pediatric patients 
• neonates 
• elderly patients

However, PCT is not indicated to be used as a stand-alone diagnostic assay and testing results should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence. In cases where the laboratory results do not agree with the clinical picture or history, additional tests should be performed.¹

Clinical perspective

"Just like any other diagnostic test, procalcitonin shouldn't be used in a vacuum. While it provides very important information, it has to be taken in the context of the signs of the symptoms of the patient and other laboratory test results."²

- Sean Neath, MD, PhD, University of California San Diego  

Plasma PCT has a normal half-life of about 24 hours and 30–45 hours in patients with severe renal dysfunction. Thus, the severity of renal failure or renal insufficiency may influence PCT values and should be considered as potentially confounding clinical factors when interpreting PCT values.³

Clinical Perspective

"[T]here has been a lot of research on it through the years with respect to the role of procalcitonin in patients with chronic kidney disease and hemodialysis. Currently, there [are] two camps of experts: One group of experts recommends a higher level of single point procalcitonin for use in these groups. And in general, whether it is untreated chronic kidney disease, stage five, or pre-dialysis or post-dialysis levels, the 0.5 cutoff is used, so it's significantly higher than in non-renal patients. I mentioned there's a second camp. The second camp also agrees that there are higher levels in chronic kidney disease and this is due to the renal clearance effective procalcitonin. Those authors recommend that a second procalcitonin [be performed] for the trending of procalcitonin. [E]ach individual patient will have their baseline as perhaps a more useful way of using procalcitonin. But there are a large number of facilities that are comfortable using procalcitonin guidance in this subpopulation, with the caveat that the cutoff levels would be higher."⁴ 

- Gregory B. Seymann, MD, SFHM, University of California San Diego

Distinguishing infection from disease flare in febrile patients with autoimmune diseases is critically important yet also challenging. Disease flare and infection have similar clinical manifestations and are identified by similar laboratory markers, such as leukocytosis and elevation of the serum C-reactive protein (CRP) level. Moreover, the leukocyte count and the serum CRP level can also be affected by systemic corticosteroid and immunosuppressive therapy.^5,6 Thus, there is an urgent need for a reliable biomarker that provides high sensitivity and specificity for the early discrimination of infection from disease flare in febrile patients with autoimmune diseases.

While administering additional or higher dosages of immunosuppressive agents can ameliorate disease flare, it can also exacerbate infection.

A meta-analysis of 9 studies showed that PCT is useful for differentiating bacterial infections from disease flares in patients with autoimmune diseases and that PCT is superior to CRP due to a better specificity for bacterial infection.⁷

Pooled sensitivity was:

• 0.75 (95% CI 0.63–0.84) for procalcitonin tests
• 0.77 (95% CI 0.67–0.85) for CRP tests.

Pooled specificity was:

• 0.90 (95% CI 0.85–0.93) for procalcitonin tests
• 0.56 (95% CI 0.25–0.83) for CRP tests.

Clinical Perspective

"… [PCT is] not impaired by neutropenia or other immunosuppressive states. But it is important that we understand the things that can make it go up that are not infection." ⁸ 

- Trevor Van Schooneveld, MD, FACP, University of Nebraska Medical Center, Omaha, NE

PCT should not be used in place of lactate as both biomarkers elevate for different reasons. PCT aids in measuring the host response to bacterial infection while lactate is a marker for tissue perfusion (i.e., mitochondrial damage). Within 3 to 6 hours of bacterial insult, PCT increases in response to bacterial infection and enables specific determination between bacterial infection and other causes of inflammatory reactions. Lactate can increase due to mitochondrial damage from infections and inflammation, but it’s not specific for bacterial infection nor does it rise until late in the course of sepsis.^5,9  For patients evaluated for a suspected infection, the combination of lactate and PCT measurements—together with clinical data and vital signs—can provide complementary information for risk stratification.^6,10

Clinical Perspective

"Many of my colleagues have asked me, ‘Should I invest in procalcitonin? Should I invest in lactate? Which one should I use?’ The regulations are talking about lactate measurements, they're not yet fully coming around to talk about procalcitonin. And I have a very simple answer to them. They are looking at two different aspects of infection. Lactate in an infected patient looks at the adequacy of perfusion. It may not be elevated even in patients with severe infections. When it is elevated, it is a guide to resuscitation. Procalcitonin, on the other side, tells you whether you have a bacterial infection or not. And so, it is a biomarker that gives different information from lactate. They have to be used in concert together to get the best results for your patient."⁸ 

- Eric Gluck, MD, Swedish Covenant Hospital, Chicago

It can be difficult deciding when antibiotics can be safely withheld or stopped, and often this leads to the unnecessary initiation or prolonging of antibiotic treatment. Additional information from PCT assays can complete the picture and objectify the decision. However, for clinicians to implement PCT testing they must be able to trust the reliability and safety of the results. As shown by institutions that incorporated PCT into their antibiotic stewardship protocols, clear guidance, education, and a multidisciplinary approach are key elements of a successful implementation. This in turn leads to a more successful antibiotic stewardship program and more judicious use of antibiotics.

Clinical perspective

"So then if we think in terms of what can we do to stop the usage, I think one of the key things that we have to look at it, we have to be able to provide enough objective critical information so that prescribers can, quote, feel comfortable enough. Many of my prescribers as they watch still feel comfortable. And so we need to give enough information and let that be objective and measurable such that they can feel comfortable enough to change their prescribing practices. Once they take that first step, then there's that adoption process. So they will consistently act on this information. And then hopefully, they will follow the algorithm because it's algorithm compliance, the more patients you can take it to the PCT algorithm to is very important."¹²

- Michael R. Broyles, BSPharm, RPH, PharmD, Five Rivers Medical Center in Pocahontas, Arkansas  

Results from two studies comparing the effect of corticoid steroids on PCT and C-reactive protein (CRP) induction confirmed previous observations^8,5 that CRP is inhibited by corticosteroids whereas PCT is not.^9,10,13,14 The data demonstrate that PCT is not influenced by short-term (e.g., after transplantation) or long-term (e.g., autoimmune disease) corticosteroid treatment.^9,10,13,14

Clinical Perspective

"[PCT] is not affected by corticosteroids. So, unlike the white count, which we have four mechanisms by which steroids drive up the white count, PCT is unaffected by corticosteroids."¹¹

- Michael R. Broyles, BSPharm, RPH, PharmD, Five Rivers Medical Center, Pocahontas, Ark.

In a patient with suspected sepsis, blood culture and PCT testing should be initiated immediately. However, according to the current guidelines, antibiotics should be started for these high-risk patients without waiting for the results.

Antibiotics should be started rapidly in these high-risk patients, independently of the PCT result, though.

However, if the PCT level was initially below 0.5µg/L, indicating low likelihood of bacterial infection, PCT should be repeated within 6-24 hours and antibiotics may be discontinued if low PCT is confirmed and the patient is clinically stable. An  aAlternative diagnosis should be considered.

For patients with elevated PCT and clinical  signs of sepsis , serial PCT testing should be performed every 24-48h to monitor the response to antibiotic therapy. D, and discontinuation of treatment should be considered when PCT has declined by at least 80% from peak value or falls below 0.5µg/L and patient is clinically improving clinically.

Clinical perspective

"In patients who are clinically unstable, or when the clinician has identified this patient is highly suspected of having sepsis, then antibiotic therapy should be initiated, regardless of the levels of PCT that have been obtained, in the event that antibiotics have been withheld based on PCT levels, and suspicion for infection should be repeated, probably somewhere between six and 24 hours after the initial levels have been obtained."¹⁶

- Eric Gluck, MD, Swedish Covenant Hospital, Chicago, IL

The sensitivity and specificity for determining bacterial infection and its severity is what differentiates PCT from other biomarkers such as lactate, C-reactive protein (CRP), blood cultures, and white blood cell count.

PCT stands out in comparison to other biomarkers by offering the following benefits:³

• Sensitivity of 89% and specificity of 94% for bacterial infection.
• Reflects bacterial burden.
• Levels are not affected by corticosteroids.
• Levels are not affected by most autoimmune diseases.
• Levels are not affected by decreasing immune function/oncology therapy.

Clinical perspective

"[Procalcitonin is] highly specific, very sensitive, and available in a timely fashion. It has really changed the landscape for both the identification of patients who are infected, and for the identification of patients who are not infected. It is a highly specific response to bacterial infections, inhibited in fact by viral infections, and therefore really aids the clinician both in its kinetics and its specificity in identifying those patients who have bacterial infections and those patients who do not."⁷

- Eric Gluck, MD, Swedish Covenant Hospital, Chicago

PCT serum concentrations are elevated in clinically relevant bacterial infections and continue to rise with the increasing severity of the disease.³  Viral infections, bacterial colonization, localized infections, fungal infections, allergic disorders, autoimmune diseases, and transplant rejection do not usually induce a significant PCT response. (Higher values above the cut off indicates the probability of having a bacterial infection, especially if it serial results are showing an increase).³ Therefore, PCT is an important marker enabling specific differentiation between a bacterial infection and other causes of inflammatory reactions.³

PCT Insights

PCT does not respond in the same way to viral infections. PCT production is attenuated by interferon gamma that is released during the host response to the virus. This is why PCT levels are low in patients with viral infections.¹²

There is significant evidence from interventional, randomized control trials as well as from real-world data that integrating PCT testing into clinical protocols helps to objectify  decision- making on antibiotic treatment. With PCT, clinicians can customize antibiotic therapy to the needs of the individual patient, resulting in lower antibiotic exposure.^18-21

Reduced antibiotic exposure leads to fewer antibiotic-related adverse events and better outcomes.  For example, a recent study indicates that limiting antibiotics exposure in the gut microbiome lowers the number of MDRO infections and related deaths.²² Thus, including PCT in the decision algorithm should help to reduce antibiotic resistance mid- to long term.

Clinical perspective

"B·R·A·H·M·S procalcitonin has provided me with a very powerful tool to aid in my decision making in antibiotic stewardship in the hospital. It helps me identify patients who are infected with more sensitivity and specificity then my previous laboratory data and clinical identification techniques could provide. It gives me for the first time an indicator of when my antibiotic therapy has been successful or not. And it reduces my consumption of antibiotics significantly in the hospital, which we hope in the long run will result in a reduction in the likelihood of creating multi drug resistant organisms that could become a nightmare for us to treat in the future."¹⁶

-Eric Gluck, MD, Swedish Covenant Hospital, Chicago, IL

Making PCT testing part of the clinical assessment and decision-making process allows clinicians to better target antibiotic prescriptions (e.g., for LRTI patients), resulting in reduced antibiotic use and shorter average duration of antibiotic therapy.

Hospitals implementing PCT into their antibiotic stewardship protocols have seen not only lower antibiotic use, but also fewer antibiotic-related side effects to be treated, better outcomes, and shorter lengths of stay. In addition, these healthcare organizations experienced net savings despite the extra costs for PCT testing.¹⁷

Clinical perspective

"How are we reducing costs in the laboratory with PCT? So I'll take that question. It's not that reducing costs in the laboratory is two ways of looking at that. So we actually reduce costs in the laboratory, even though we ran procalcitonin a ton. And because the patients are getting well quicker, the patients aren't staying as long we're using fewer resources. So while we're investing a little bit of money in procalcitonin, we're actually seeing less need to work to do more diagnostic workup later on in the course of the disease. So essentially, because we're headed in the right direction, we can know that we're heading in the right direction, we're not have to run more tests and swim hearts. And we've seen this over and over again, one of the things that we didn't report is we actually had a 13% in inpatient radiology procedures, because they're not doing as many films and studies because essentially, the patients are doing better. And I know that like you're the physician, you could address that also. But since I oversee lab, that's one of the things I look at. And when I look at the procedures per patient, they're actually fewer because we're actually doing a better job of taking care of them, I think. Yeah, I reiterate that because not only are we doing less tests, specifically for that disease, we're doing less monitoring to there are a few patients getting ankle myosin, those things which require monitoring of levels and other antimicrobials, they require monitoring of levels, they spend less time in the ICU and typically, in the ICU, besides doing the standard laboratory with doing surveillance laboratory. And if they spend less time there, we don't need to do that either. I think we need to get away from this archaic way of looking at cost, in that most hospitals, it's siloed. And people will look at the laboratory as an increase of a laboratory cost based on PCT of maybe $20 a day. But in reality, if you take away one day of antimicrobial therapy, or two days of their microbial therapy, which comes from a different cost centers, that way offsets the increased cost of the procalcitonin. And then if you can get one, one patient out of the hospital a day earlier, you bought I'm not laboratory tests for probably 10 patients with sepsis. So the point of the matter is, is that you can't just look at the cost of an individual test as a negative, you have to look at the intended consequences of that cost. And the unintended consequences of that cost, which actually, paradoxically, can make things look very differently. Like for instance, patients might actually ends up being treated for an extra day or two for a disease. But when you treat that person for an extra day or two, and they don't get a recurrence, that actually may result in a significant cost savings. "¹²

- Michael R. Broyles, BSPharm, RPH, PharmD, Five Rivers Medical Center in Pocahontas, Arkansas

There are a number of benefits for hospitals and their patients from the implementation of PCT testing as part of an antibiotic stewardship program. These include the following:

• PCT gives clinicians a tool to objectify antibiotic decision-making and tailor antibiotic therapy to the needs of each patient. This results in an overall reduction in antibiotic use.
• With less antibiotic exposure, patients experience fewer side effects (such as C. diff, MDRO, organ toxic effects, etc.) and better outcomes.
• More appropriate use of antibiotics plays a critical role in reducing antibiotic resistance.
• Though there are extra costs associated with implementing a PCT testing protocol, hospitals still see net savings.

Clinical perspective

"So to anyone considering adding PCT to your program, it's a no brainer. When you can actually shorten the amount of antibiotics you use, shorten the duration of a patient's stay, reduce adverse events, reduce c diff, reduce mortality, all of the the addition of a test. It makes no sense not to do it."²³

- Michael R. Broyles, BSPharm, RPH, PharmD, Five Rivers Medical Center in Pocahontas, Arkansas

The inappropriate use of antibiotics—whether overprescribed or used for too long—has resulted in a global crisis of antibiotic resistance. Patients with an infection caused by a resistant pathogen are more difficult to treat, face a higher risk of adverse outcome, require longer hospital stays, and incur significantly higher costs to the health care system.

The use of PCT can lead to a more judicious use of antibiotics and help reduce the spread of antibiotic resistance.

Clinical perspective

"So when we think about the economic consequences, quite simply just very simple terms as resistance equals more expensive antibiotics for combinations of antibiotics, longer length of stay, the single biggest driver costs in a hospital is length of stay. And then we look at adverse drug events, I mean this you'll see that the range here is 28,000 to 8000, essentially, on most adverse drug events on the solid adverse drug events are in that 32,000 or 3200 plus range. So they can be very expensive, very costly to hospitals. We look at the cost of C. difficile infection. Obviously, this can be very high. And then I think one of the big things is that people sometimes under appreciate is that CMS when we look at Clostridium difficile infections, many hospitals are losing up to 1% of their Medicare money, you think, Oh, 1% doesn't seem like a lot. But 1% on top of millions of dollars, we can hundreds of 1000s of dollars. And that's a very expensive proposition for us. Again, on top of that, the readmissions that are being paid for and the readmission. And one thing I would like to drive home is that we do have things can change that and this is the use of PCT algorithms, and the use of those consistently can reduce these expansion expenditures and save us money and resources."¹²

- Michael R. Broyles, BSPharm, RPH, PharmD, Five Rivers Medical Center in Pocahontas, Arkansas

PCT levels may not be elevated in patients infected by certain atypical pathogens, such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.¹³²⁴

There are situations and conditions where PCT can be elevated by non-infectious causes. These include, but are not limited to:^3,14-1625-27

• Patients experiencing major trauma and/or recent surgical procedure including extracorporeal circulation or burns.
• Patients under treatment with OKT3 antibodies, OK-432, interleukins, TNF-alpha and other drugs stimulating the release of pro-inflammatory cytokines or resulting in anaphylaxis.
• Patients diagnosed with active medullary C-cell carcinoma, small cell lung carcinoma, or bronchial carcinoid.
• Patients with acute or chronic viral hepatitis and/or decompensated severe liver cirrhosis (Child-Pugh Class C).
• Patients with prolonged or severe cardiogenic shock, prolonged severe organ perfusion anomalies or after resuscitation from cardiac arrest.
• Patients receiving peritoneal dialysis or hemodialysis treatment.
• Patients with biliary pancreatitis, chemical pneumonitis or heat stroke.
• Patients with invasive fungal infections (e.g., candidiasis, aspergillosis) or acute attacks of plasmodium falciparum malaria.
• Neonates during the first 72 hours of life.

Clinical Perspective

"But it is important that we understand the things that can make [procalcitonin] go up that are not infection. And that's what I want to talk about next. Because procalcitonin is driven by systemic cytokine release, any major event that causes significant systemic cytokine release is going to make your procalcitonin level go up. Now, if you remove that stimulus, it'll go back down. And so, some of those things are like major physiologic stress. And it turns out that being born is a major physiologic stress. And so, within the first [48] hours after birth, it's a little difficult to interpret procalcitonin levels. But generally, after that, we interpret them as normal. Any major stress like severe trauma, surgery, cardiac shock, burns, anything like that is going to cause your procalcitonin go up. Now, if you remove that stress, it'll then go back down. And there's tons of literature in the surgery literature, showing protocols and levels that are normal before surgery, they have a major cardiac surgery, liver transplant surgery, the levels go up, and then come back down as long as an infection does not develop. And then any prolonged severe non-resolving cardiogenic or shock abnormality, or organ perfusion abnormality has not been resolved, is going to continue to drive procalcitonin level being elevated. And so non-resolving cardiogenic shock will make your procalcitonin level go up. And unless it gets fixed, it's going to stay up.

There are some nonbacterial cytokine activation syndromes where you can see this go up. Certain forms of vasculitis and acute graft versus host can make procalcitonin go up. Malaria and systemic fungal infections like candidemia can cause it to be elevated. Now, those are infections and so that is somewhat helpful. And then chronic renal disease and we should discuss briefly about chronic renal disease. Chronic renal disease, particularly being on dialysis is a generally pro-inflammatory state. And so, if you look at any biomarker, CRP, things like that, they're going to be mildly elevated in people on dialysis. And so that's generally what we see in people on dialysis or people with acute kidney injury is that procalcitonin levels will be mildly elevated. So, the 0.25, 0.5, even up there may be 1-ish. But really high levels, and really low levels are still meaningful. A procalcitonin level that's undetectable, is a procalcitonin level that’s undetectable and we can use that. A procalcitonin level that's 20. That's really high and I wouldn't attribute that to renal disease and so we can use that. And then there's some dysregulated syndromes where we can give some agents that might stimulate cytokine production, particularly some of our organ transplant induction agents, granulocyte transfusions and then paraneoplastic syndromes where you produce calcitonin, you're going to have elevated procalcitonin levels."¹⁶

- Trevor Van Schooneveld, MD, FACP, University of Nebraska Medical Center, Omaha, Neb.

In a large proportion (50.2–67.1%) of cases with CAP diagnosis, no pathogen is detected despite extensive microbiologic evaluation.²⁸ As a result, it’s difficult to correctly estimate the true incidence of bacterial CAP.

However, when a bacterial pathogen is detected in patients with CAP, the one found most frequently is Streptococcus pneumoniae (pneumococcus). A recent review of 146 papers (82,674 patient data sets) found Streptococcus pneumoniae in 33–50% of all cases in which an etiology was established, with declining frequency over the years and high geographic variability (e.g., there were significantly lower values in the USA and Canada versus Europe).²⁸

According to the review, the incidence of other typical bacterial pathogens was as follows:

• Haemophilus influenzae: 7–16% of cases
• Staphylococcus aureus and Enterobacteriaceae including Klebsiella were implicated with approximately equal frequency (4–10%).
• Pseudomonas (0.8–4.5%) and
• Moraxella (1.2–3.5%) were less common causes
• Other bacteria were isolated far less frequently.

Among the so-called “atypical” bacteria, Mycoplasma caused about 4–11% of CAP, Legionella 3–8%, Chlamydophila 2–7%, and Coxiella < 2%.

Viruses were found in about 10% of case series, but recent reports that included viral PCR on most or all patients found a respiratory virus in about 30% of cases, with bacterial/viral coinfection being relatively common.

Note that the relative prevalence of the CAP pathogens varies with geography, pneumococcal vaccination rates, host risk factors (e.g., smoking), season, and pneumonia severity.²⁹

Clinical perspective

“[Let me] point out a couple of facts for you some things to think about. So, this was from a Medscape review article that came out at the end of last year. And this is talking about community acquired pneumonia. That's what this says, it says pinpointing the source of infection, and community acquired pneumonia can be a daunting task, but more often than not, results in failures. Although streptococcus pneumonia are the most frequently isolated bacterial pathogens, this is the key, note, this sort what it says, bacterial pathogens, they are no longer the most common cause of CAP. In fact, despite extensive testing, no pathogen is detected in 60% of patients with CAP, we've known this all along. I mean, we are very, very fortunate if we can come up with an ID of 40% of the organisms that cause community acquired pneumonia. But notice what it says. Even when a pathogen is isolated, it's usually a rhinovirus, an influenza virus or human metapneumovirus. This is due in part to the use of vaccines. So where historically we used to always think in terms of community acquired pneumonia, and we would say, Okay, this is a bacterial etiology, that's no longer the case. And this kind of brings us up with something to think about. The environment has changed, and this allows us opportunities to avoid prescribing antibiotics and cure viral infections.” ¹²

- Michael R. Broyles, BSPharm, RPH, PharmD, Five Rivers Medical Center in Pocahontas, Arkansas

For patients in the ED, PCT can help clinicians assess the likelihood of relevant bacterial infection and the risk for progression to a more severe disease state, information which can drive the decision to admit the patient.^30,31

Monitoring PCT levels in those patients who are admitted and receive antibiotics reveals important data about the course of the bacterial infection, the response to antibiotic therapy, and the prognosis.

One of the decision criteria for discontinuing antibiotics is a decline in the PCT level of 80% from peak value. ^32,33 To get this information, it’s necessary to obtain PCT results at the earliest point in time—i.e, when the patient enters the ED. With PCT testing in the ED, clinicians gain a baseline for the assessment of therapy response and for further decision- making.

Clinical perspective

“The initial procalcitonin taken on day zero in the emergency department also provides important initial baseline for comparison to the procalcitonin values done by downstream providers in the hospital. Similar to the way that we draw blood cultures in the emergency department so that our colleagues have more information to manage that patient procalcitonin baseline day zero, will undergo some dynamic changes during the hospital course. And that baseline that we draw in the emergency department will provide useful information for the clinicians who do subsequent draws in the ICU or other hospital settings.” ⁸

- Trevor Van Schooneveld, MD, FACP, University of Nebraska Medical Center, Omaha, NE

To assess treatment success and to support a decision to discontinue antibiotic therapy, follow-up PCT samples should be tested once every 1 to 2 days, based upon a physician’s discretion and taking into account the patient’s evolution and progress.^{23-25, 32-34}

Antibiotic therapy may be adjusted using the discontinuation table below:

Decisions regarding antibiotic therapy should NOT be based solely on PCT concentrations.¹ Antibiotic therapy may be continued based upon other clinical findings, such as apparent progression on chest X-rays or ongoing or increasing toxicity.¹

If the clinical picture has not improved and PCT remains high, re-evaluate and consider treatment failure or other causes.¹

For the detection of subtle changes in PCT in patients with LRTI or sepsis, the use of sensitive and precise PCT assays is recommended.¹

PCT Insights

PCT supports the decision whether or not to initiate antibiotics. For example, in patients with symptoms of lower respiratory tract infections, or LRTI, PCT levels > 0.25 ng/mL suggest likelihood of bacterial infection and antibiotics should be initiated. The trend of PCT values over time can help to decide the right time to stop antibiotics. After a measurement on admission, it is recommended to remeasure PCT every 24 to 48 hours. It [may] a safe time point to stop antibiotics when the patient becomes clinically stable, and PCT declines more than 80% below the peak observed value, or PCT declines below an absolute threshold of ≤ 0.25 ng/mL in LRTI patients, or ≤ 0.50 ng/mL in sepsis patients. Numerous clinical studies have shown that this approach is safe and effective for avoiding unnecessary antibiotic treatment.²³