Distinguishing between viral and bacterial pneumonia remains a challenge in medical practice.1 Without a reliable method to discern the accurate diagnosis, clinicians tend to overprescribe antibiotics for suspected bacterial pneumonia cases, even when they are purely viral in etiology.2 This behavior in turn drives antibiotic resistance.3 There has been great emphasis on identifying useful serum biomarkers to address this diagnostic deficiency. Indeed, upon acute infection, several inflammatory markers, such as CRP and IL-6, increase in the bloodstream.4 Although these were shown to carry prognostic value for the clinical outcome,5 they constitute only a nonspecific response to both bacterial and viral infections. Therefore, they cannot be used to distinguish between the two etiologies.6,7 Certain other biomarkers were shown to offer both diagnostic and prognostic information. Most prominently, clinicians can use white blood cell count differential assays, where leukopenia is associated with viral infections and neutrophilic leukocytosis is associated with bacterial infections.8 Further, resolution of the abnormal cell counts is known to correlate with clinical improvement and infection resolution.9 Regarding diagnostics alone, perhaps the most specific approach is the application of a multiplex PCR panels that screen for specific viruses and bacteria.10,11 Other laboratory studies such as serum pneumococcal antigen and urine legionella antigen are also being of commonly utilized.12

The focus of this systematic review is the biomarker procalcitonin, which had been evaluated in numerous clinical trials, some of which show promising results for the differentiation between bacterial and viral pneumonia as well for the guidance of antibiotic cessation.

Procalcitonin is a 116-amino acid precursor to the 32-amino acid hormone calcitonin, which lowers serum calcium levels. It was first described by Copp et al. in their study of a dog animal model.13,14 Procalcitonin was first recognized as a possible diagnostic biomarker for sepsis and bacterial infections in 1993.15 In a healthy individual, the procalcitonin concentration is normally below 0.1 ug/L but it increases in the presence of a bacterial infection, with higher concentrations usually correlating with greater infection severity.16 In health, procalcitonin is mainly produced by thyroid C-cells. However, during bacterial infections, procalcitonin was shown to be synthetized inside the intestines, lungs, pancreas, liver, kidney by leukocytes.17 On the other hand, in the case of a viral infection, cytokines such as interferon γ are released and lead to the down-regulation of procalcitonin.18 Sometimes, a confounding condition may exist that causes procalcitonin to be elevated at baseline, without an ongoing infection. This can occur in patients with chronic kidney disease, severe trauma and burns, or a recent major surgery.16

In the USA, the Food and Drug Administration has approved the use of procalcitonin to guide antibiotic treatment for lower respiratory tract infections, such as pneumonia,19 although its usefulness in clinical decision-making still awaits to be confirmed. Given the much higher level of medical malpractice litigation in the USA compared with Europe,20,21 one might expect that US-based clinicians would be less likely to use the biomarker procalcitonin to withhold or stop antibiotics for suspected bacterial pneumonia. However, to date, no such comparison has been performed. Here, we provide a systematic literature review covering the research accumulated over the last decade on the application of procalcitonin for the management of pneumonia in the United States and Europe.