Current Review of the Significance of Procalcitonin in the Diagnosis and Therapy of Pulmonary Infections

Antimicrobial resistance is responsible for 700,000 deaths per year worldwide, and a progressive rise is foreseen with predictions rising up to 10 million deaths globally by 2050. In addition, healthcare-associated infections (HAI) affect 4.5 million patients worldwide, prolong Length of Stay (LOS) by 16 million days, and are responsible for 37,000 deaths each year in Europe. The annual cost of antimicrobial resistance and HAI in the European Union is estimated at between1.5 and 7 billion euros, respectively. The maximum exponents of this situation are the intensive care units, where vulnerable critically ill patients require invasive devices and receive more antibiotics [1-3]. The unnecessary prescription and prolonged durations of antibiotic therapy are global issues that lead to antibiotic resistance [4]. These two issues are particularly prevalent in the management of acute respiratory tract infections (ARTIs) [5,6]. Procalcitonin (PCT) is a serum-biomarker and its kinetics are linked to the phases of bacterial caused infections. PCT-serum levels rise quickly in the early phase of bacterial infection, peak within 2-4 hours and decrease with the resolution of infection. A viral etiology causes low rises of PCT-levels and therefore PCT can be used to differentiate bacterial infections from other triggers of inflammation [7,8]. This narrative mini-review aims to inform about the significance of decision-making guided by PCT levels in diagnosis and therapy of ART by briefly reviewing PCT-focused studies.


Introduction
Antimicrobial resistance is responsible for 700,000 deaths per year worldwide, and a progressive rise is foreseen with predictions rising up to 10 million deaths globally by 2050. In addition,

Community-Acquired Pneumonia (CAP)
Among all infectious diseases in the western world, pneumonia is the leading cause of deaths [9]. Clinically, CAP is associated with with productive cough, high fever and shortness of breath and is diagnosed by a proper physical examination and consolidation in the chest X-ray. Although CAP is mostly caused by bacteria, up to 20% of all CAP have viral etiologies [10]. By using a threshold of 0.1ng/mL, PCT is 80% sensitive and 51% specific in the detection of any bacterial pathogen. The levels are higher in patients with typical compared to those with atypical pneumonia [11]. Analysis of PCT levels can serve as an aide to clinical evaluation and imaging in uncertain cases. But there are no defined thresholds which are reliable enough to rule out pneumonia caused by bacterial infections reliably . Since CAP is associated with a very high morbidity, antibiotics should not be withheld on the basis of PCTlevels alone [12].
The main significance of PCT might lie in the cessation of antibiotic therapy in response to decreasing serum PCT-levels which occur with the resolution of an acute bacterial infection. The ProCAP -study, a prospective, single-blinded, randomized study, showed that by analyzing regular PCT-levels of an ongoing infection and following a PCT-guided algorithm, the Days of Antibiotic Treatment (DOT) were reduced to 6 days in the PCT-group compared to 13 days in the guideline-conform group with both groups having comparable outcomes [13]. The ProHOSP study showed a lower, but still significant reduction of DOT (10.7 to 7.2 days) by using a PCT-algorithm in patients with CAP [14]. PCT-guided antibiotic discontinuation did not result in increased adverse events [15] and may cause lower costs in the medical sector and could be a relevant contributor in the fight against rising antimicrobial resistance.

Acute exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
AECOPD is characterized by a sudden worsening of prior existing cough, sputum production and dyspnea. Infectious agents trigger most of the acute exacerbations (70%) and bacteria are the main cause, but 30-50% of all infectious-triggered exacerbations have a viral etiology [16] COPD-patients are very likely to be prescribed antibiotics during an acute exacerbation. While some studies show that different cut-off PCT-levels indicate a bacterial etiology [17,18], there are several studies concluding that PCTlevels are not significantly higher in bacteria-caused exacerbations and therefore PCT-levels may not be reliable to distinguish between bacterial and other etiologies [19,20].
AECOPD is linked to a high mortality and antibiotic therapy should therefore not be delayed by PCT-levels due to the uncertainty about serum thresholds and their reliability to discriminate bacterial triggers from other causes of exacerbation. Regarding a PCT-guided initiation of antibiotic therapy in AECOPD patients, the ProResp-study showed a 50% of all antibiotic prescriptions in the emergency department [21]. But a multicenter, randomized trial with 302 patients admitted to the ICU resulted in higher 3-month mortality in the PCT-group and did not reduce the period of antibiotic exposure [22]. PCT-guided decision making concerning the initiation of antibiotic therapy in AECOPD remains therefore highly controversial. Regarding discontinuation of an antibiotic therapy, Bremmer et al. concluded that using a PCT-driven algorithm can shorten the DOT (5.3 vs. 3.0 days) and does not result in a higher 30-day readmission rate in AECOPD patients [23]. Other studies also showed similar decrease of DOT in their AECOPDsubgroup if a PCT-guided management was performed [24]. In the ProCOLD-study PCT-guided antibiotic management resulted in the decrease of antibiotic usage for up to 6 months [25]. A recent meta-analysis including 7 RCTs (n=1287) regarding antibiotic use suggested that the use of PCT-guided antibiotic therapy in patients with AECOPD can effectively reduce antibiotic prescriptions and shows similar efficacy and safety for other parameters compared with standard antibiotic therapy. However, according to the review, it does not reduce antibiotic exposure duration or antibiotic use after discharge [26].

Acute Bronchitis
Acute bronchitis is a self-limiting acute respiratory infection.

Conclusion
PCT has developed into a promising new biomarker for early detection of (systemic) bacterial infections. Procalcitonin has utility in a number of clinical scenarios in airway infections such as CAP, however, current research suggests that among these use cases, PCT levels are most useful in the setting of AECOPD patients to determine when and if antibiotics should be initiated.