Jan 032013
Procalcitonin to Guide Treatment of Pneumonia
(More PulmCCM Topic Reviews)

With mounting evidence for its utility as a biomarker for pneumonia, procalcitonin is one of the hottest 2012 topics in pulmonary & critical care. Procalcitonin tends to rise quickly as bacterial infections (but not viral infections) develop, increase with the severity of infection, and decline as bacterial infections resolve. Procalcitonin is far from perfect, and should only support clinical judgment, not replace it. However, procalcitonin testing increasingly appears to be a useful tool to help physicians prescribe antibiotics to the right patients, and to stop antibiotics when they're no longer helpful.

Diagnosing Respiratory Infections: the Need for Biomarkers

Respiratory infections are the most common illnesses in people, and the most common cause of sepsis. Faced with the patient with a likely respiratory infection, a physician is often faced with an impossible task: giving antibiotics to the minority of patients with bacterial pneumonia, who are at risk for clinical worsening or even death without drug treatment, while avoiding overprescription of antibiotics for the large majority of patients with viral respiratory infections. Clinical signs, symptoms, rapid microbiologic testing, and imaging are largely unreliable in differentiating viral from bacteria pneumonias and other infections. Researchers have long sought laboratory biomarkers that could accomplish this task, and in so doing improve antibiotic use and clinical outcomes.

What Is Procalcitonin?

Under stimulation from cytokines, multiple tissues release procalcitonin in response to bacterial infection within 6 to 12 hours; procalcitonin is more specific than C reactive protein or the white blood cell count. More severe infections tend to produce higher levels of procalcitonin. Further, viral infections tend to increase the cytokine interferon-gamma, which inhibits procalcitonin release--resulting in lower levels of procalcitonin during viral infection. During resolution of bacterial infections, procalcitonin levels tend to steadily fall (by 50% daily or so), returning to very low or undetectable levels when a bacterial infection resolves completely. Procalcitonin seems to be unaffected by corticosteroid therapy, unlike many other markers of immune system activity. (AACC's procalcitonin primer)

Thus, procalcitonin holds promise in distinguishing bacterial from viral infections, and for measuring the severity of a bacterial infection, and charting its resolution and cure. However, procalcitonin can also be stimulated by cytokine release in the absence of infection--as after trauma or major surgery--but procalcitonin steadily falls during recovery.

Procalcitonin testing currently costs about $25 to 30 per assay in the U.S. Cut-off procalcitonin levels for high/low probability of infection are not standardized, and vary between labs and clinical settings. In some clinical trials, procalcitonin > 1 mcg/mL has been used as a "high likelihood" of infection, <0.25 mcg/L as "low likelihood," and 0.50 mcg/L as a point of indetermine probability. Only high-sensitivity procalcitonin assays should be used to make important clinical decisions.

Can Procalcitonin Diagnose Respiratory Infections?

It is impossible to determine the test performance characteristics of procalcitonin (or any other biomarker) for diagnosing infections, because there is no reference/gold standard for the diagnosis of infection. Our highest-specificity tool--microbiologic culture--is just not sensitive enough: bacteria are only identified in 10 to 20% of respiratory infections, and in less than 50% of cases of sepsis.

However, it seems clear from the best published studies that procalcitonin is not sufficiently accurate to consistently differentiate bacterial from viral pneumonias, or (most likely) any other infection. Examples: procalcitonin's ~10% false negative rate in identifying bacterial superinfection of viral pneumonias; its insensitivity to Mycoplasma pneumonia; and the complete uncertainty surrounding its performance in diagnosing healthcare or ventilator associated pneumonias.

Clinical Takeaway: In cases of suspected pneumonia or other infections, procalcitonin should be used as supporting information only, not as a definitive diagnostic test. An example would be a very high procalcitonin helping to increase a physician's confidence in the diagnosis of bacterial pneumonia.

Procalcitonin To Reduce Antibiotic Overuse

Lacking a gold standard to prove procalcitonin's utility in diagnosis of infection, procalcitonin has been tested in more than a dozen randomized trials in a variety of settings (clinic, hospital ward, ICU) to see if its use can reduce antibiotic prescriptions without worsening clinical outcomes.

In nearly all these trials, use of a procalcitonin-guided algorithm to start and/or discontinue antibiotics reduced antibiotic exposure--usually by about 50% of the total doses--without any increase in mortality or any other (detectable) adverse event. Meta-analyses confirmed these benefits and could not uncover any risk from the use of procalcitonin. While reassuring, confidence intervals were wide in these studies, and many ICU patients were excluded from the procalcitonin protocols by their physicians.

Clinical Takeaway: Larger trials are probably needed to conclude procalcitonin should guide antibiotic therapy as standard care, but physicians who choose to do so can be encouraged by the favorable data suggesting guidance by procalcitonin safely reduces antibiotic overuse.

Proposed Uses of Procalcitonin Testing

In the July 2012 Chest, Philipp Schuetz et al argue that the benefits of procalcitonin testing are well enough established, and its risks sufficiently low, that physicians should feel comfortable using procalcitonin to help make clinical decisions in the workup of suspected respiratory infections.

Schuetz et al propose several scenarios in which procalcitonin can guide antibiotic therapy:

  • For patients in clinics and emergency rooms whom physicians see as low-probability for bacterial infections, a procalcitonin level of <0.25 mcg/L should be safe to exclude bacterial infection and withhold antibiotics. They suggest repeat testing for anyone who feels or looks worse several hours later. If procalcitonin is > 0.25 mcg/L (or "particularly 0.50 mcg/L"), bacterial infection is more likely.
  • Patients in the E.D. or admitted to the hospital with a suspected pneumonia and procalcitonin > 0.25 mcg/L should be assumed to have bacterial pneumonia, authors say. Antibiotics should not be delayed simply while waiting on procalcitonin levels (unless the test can be resulted rapidly, within an hour or 2 of presentation), authors suggest. Procalcitonin < 0.25 mcg/L does not rule out bacterial infection, but makes it much less likely.
  • For ICU patients or others with more severe infections, the decision-making process shifts. For patients who are clinically deteriorating, antibiotic therapy should not be delayed while waiting on a procalcitonin result. Authors suggest that an initial procalcitonin level < 0.5 mcg/L should raise suspicion of non-bacterial infections or other causes of distress. Measuring serial procalcitonin levels may be most useful, in order to understand the trend, identify the peak, and be able to identify resolution of bacterial infection (if present). Authors suggest checking a second level after 6-24 hours.
  • For severely ill patients who have improved significantly, a fall of procalcitonin to <0.5 mcg/L or by 90% of its initial value should provide reassurance that antibiotic therapy can be safely stopped, authors say.
  • After trauma, major surgery, or cardiogenic shock, procalcitonin levels may rise in the absence of any infection, due to a cytokine stress response to injury. For such patients who are receiving empiric antibiotics and improving clinically, authors suggest using procalcitonin trends to support early discontinuation of antibiotics.

With gratitude to: Schuetz P et al. Role of Procalcitonin in Managing Adult Patients With Respiratory Tract Infections. Chest 2012;141:1063-1073.

Procalcitonin meta-analysis & review

Procalcitonin and CRP as infection biomarkers 

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Can procalcitonin help guide therapy for suspected pneumonia & other infections? (Review)