The Molecular Basis of Procalcitonin Synthesis in Different Infectious and Non-Infectious Acute Conditions

Abstract

Bacterial infections: By and large PCT levels are elevated in bacterial infections as reported by several studies, but the feature of the response can be different. For example higher peak PCT concentrations are expected in Gram negative as compared to Gram positive infections. Furthermore, differences may also be seen even within the family of Gram negative bacteria: as higher peak PCT concentrations can be detected in Enterobacteriaceae, as compared to non-fermentative Gram negatives or obligate Gram negative anaerobes. 5, 6 This is due to the polymorphism of the pathogen associated molecular patterns (PAMP) resulting in slightly different cytokine profiles hence different PCT values. In neutropenic patients, as the vast majority of the PCT synthesis is originated from the monocytes and macrophage cells, an attenuated response is expected with lower PCT levels 7-11. Viral infections: Linscheid and coworkers has shown in differentiated adipocyte cell culture that addition of interleukin-1 beta (IL-1β) has induced the synthesis of PCT while the addition of IL-1β and interferon-gamma (IFN-γ) concomitantly has blocked it 12,13. In viral infections the host T helper lymphocytes are forced to produce IFN-γ which has a negative feedback effect on the synthesis of (IL-1β), which is the main trigger of PCT induction. However, peak PCT concentrations would very seldom reach that of seen in bacterial infections. This is also true for chronic viral infections as can be seen in HIV infections, the peak concentration and the cutoff are considered to be lower 14,15. The discriminative effect of the PCT can be used in the clinical practice as described in the French and German guidelines for the management of meningitis 16,17 and in the antibiotic reduction in case of lower respiratory tract infections (LRTI) 18 , (Figure 1). Nevertheless, it is also important to acknowledge that bacterial super-, or co-infections can facilitate the synthesis of PCT, which makes the interpretation of PCT results more difficult under such circumstances, therefore, detailed clinical and microbiological assessment of the patient is inevitable to make appropriate decisions. Fungal infections: Initially it was considered in a paper by Huber that PCT has no value in invasive fungal infections 19,20. This was based on the finding that the magnitude of PCT elevation was far less than expected. However, more recent results reported that there may be a detectable PCT response in certain cases of invasive fungal infections, although there are substantial differences in the PCT levels found 5,21,22. This could be due to the different host response to different Candida species, which should be tested by further studies 23. One of the reasons why PCT concentrations are lower in fungal infections than in bacterial infections is the increased synthesis of IFN-γ and IL-17 as part of the intact immune response for fungal infections, both of which are able to decrease/block the induction of PCT synthesis 24. In cases of mixed bacterial-fungal infections, often seen in intensive care patients, we face similar diagnostic difficulties as discussed in the previous paragraph. As the blocking effects of IFN-γ and interleukin-17 (IL-17) on PCT production can be overwhelmed by host's response for bacterial super-infection, PCT synthesis can be detected but the magnitude may be lower than seen in bacterial infection only. To overcome this diagnostic challenge the complex