SAGE IVD recommended inclusion on the EDL of the test for procalcitonin levels in serum and plasma, noting the strong evidence for its quality and performance and the flexible assay formats and levels. SAGE IVD considered that guidelines or an algorithm are required for its use, although the complexity and variability of sepsis might make this difficult. The test should therefore be used only in tertiary care facilities where physicians are available to modify or override decision thresholds where required in view of clinical presentation and patient characteristics. Recommended test purpose: to guide antibiotic therapy initiation or discontinuation in sepsis and lower respiratory tract infection (for use only in tertiary care facilities).

The evidence that the procalcitonin test could reduce the use of antibiotics appears to be strong and justifies its use in diagnosis and during treatment to contribute to a decision on starting and discontinuing antibiotics. While data on reductions in mortality rates varied by setting and condition, showing either a reduction or no effect, there was no evidence that reducing antibiotic use put patients at risk of harm. Although the accuracy of diagnosis of sepsis was not high and while a single measurement could predict progression to severe sepsis but not mortality, the test-treatment trials provide convincing evidence that use of the test benefits patients and reduces antibiotic use. No comparison has been reported of procalcitonin with other, cheaper biomarkers, such as C-reactive protein, which can be used for the same purpose.

Key supporting evidence was contained in a Cochrane review of randomized clinical trials (RCTs) of procalcitonin test strategies used to initiate or discontinue antibiotics in acute respiratory infections (8). The review comprised 32 RCTs with analysis of data on individual participants in 26 and a total of 6708 participants. The main benefits were a 2.4-day reduction in exposure to antibiotics (5.7 versus 8.1 days, 95% CI –2.71 ; –2.15, P < 0.001) and a lower risk for antibiotic-related side-effects (16.3% versus 22.1%, adjusted odds ratio 0.68, 95% CI 0.57 ; 0.82, P < 0.001). No difference in mortality was noted in 11 trials in emergency departments (76/1892 versus 79/1913) (RR=0.97 (0.70, 1.36), no heterogeneity), but a reduction in mortality was evident in 16 trials in intensive care units (530/2617 versus 586/2616) (RR=0.88 (0.77, 1.00), no heterogeneity). No significant difference was found in treatment failure (procalcitonin test 23.0%, control group 24.9%). The length of stay in hospital and in intensive care units was similar. Data were presented only for mortality and treatment failure; however, additional data to support the conclusion on antibiotic use and side- effects were provided to the SAGE IVD by the authors of the review. A second Cochrane review of RCTs of procalcitonin test strategies used in adults with sepsis, severe sepsis or septic shock (9) comprised 10 RCTs published up to 2015, with a total of 1215 participants. The mean time to receiving antimicrobial therapy in the intervention groups was reduced by 1.28 days with procalcitonin testing (95% CI: –1.95 ; –0.61). The mortality rate was reduced at the longest follow‐up (RR=0.81 (0.65–1.01)) and at 28 days (RR 0.89, (0.61–1.31)) but not at discharge from intensive care (RR 1.03 (0.5– 2.11)) or hospital (RR 0.98 (0.75–1.27)). None of the primary studies had included an analysis of a change in antimicrobial regimen from a broad to a narrower spectrum. The authors considered that the inevitable lack of blinding in test-treatment trials incurred a risk of bias, which was not considered a concern by SAGE IVD.

World Health Organization. (‎2019)‎. The selection and use of essential in vitro diagnostics: report of the second meeting of the WHO Strategic Advisory Group of Experts on In Vitro Diagnostics (‎including the second WHO model list of essential in vitro diagnostics)‎. World Health Organization. https://iris.who.int/handle/10665/329527