Abstract: From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta-analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic-related side effects. Primary endpoints: there were 286 deaths in 3336 procalcitonin-guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin-guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin-guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI -2.71 to -2.15, P < 0.001) and lower risk of antibiotic-related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate-data analysis based on all 32 eligible trials showed similar results. This updated meta-analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high-quality research is needed to confirm the results in immunosuppressed patients and patients with non-respiratory infections.

Plain-language summary: All included trials randomised participants with acute respiratory infections to receive antibiotics based on procalcitonin levels ('procalcitonin-guided' group) or a control group. The trials were performed in primary care, the emergency department and medical wards, and the intensive care unit. Included participants had acute upper or lower respiratory infections, including pneumonia, bronchitis, exacerbation of chronic obstructive pulmonary disease, and others. All studies were investigator-initiated trials. Half of the trials were funded by national agencies or did not report funding, and half of the trials received funding from the biomarker industry (e.g. Thermo Fisher Scientific). We studied 6708 participants from 26 trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided participants compared to control participants (286 deaths in 3336 procalcitonin-guided participants (8.6%) versus 336 deaths in 3372 controls (10.0%)). There was no significant difference with regard to treatment failures. Results were similar for different clinical settings (primary care, emergency department, intensive care unit) and types of respiratory infection. Regarding antibiotic exposure, participants in the procalcitonin-guided group had a 2.4-day reduction in antibiotic exposure and a reduction in antibiotic-related side effects (16.3% versus 22.1%). The quality of the evidence was high for mortality and antibiotic exposure. Most of the trials did not use blinding, however we did not expect that mortality would be biased by this limitation. The quality of the evidence was moderate for treatment failure and antibiotic-related side effects because the definitions for these endpoints among trials were not identical.