Cochrane Library   Cochrane Database of Systematic Reviews   Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review)     Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wol& M, Chastre J, Tubach F, Kristo&ersen KB, Burkhardt O, Welte T, Schroeder S, Nobre V, Wei L, Bucher HCC, Bhatnagar N, Annane D, Reinhart K, Branche A, Damas P, Nijsten M, de Lange DW, Deliberato RO, Lima SSS, Maravić-Stojković V, Verduri A, Cao B, Shehabi Y, Beishuizen A, Jensen JUS, Corti C, Van Oers JA, Falsey AR, de Jong E, Oliveira CF, Beghe B, Briel M, Mueller B     Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wol& M, Chastre J, Tubach F, Kristo&ersen KB, Burkhardt O, Welte T, Schroeder S, Nobre V, Wei L, Bucher HCC, Bhatnagar N, Annane D, Reinhart K, Branche A, Damas P, Nijsten M, de Lange DW, Deliberato RO, Lima SSS, Maravić-Stojković V, Verduri A, Cao B, Shehabi Y, Beishuizen A, Jensen JUS, Corti C, Van Oers JA, Falsey AR, de Jong E, Oliveira CF, Beghe B, Briel M, Mueller B. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database of Systematic Reviews 2017, Issue 10. Art. No.: CD007498. DOI: 10.1002/14651858.CD007498.pub3.     www.cochranelibrary.com   Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review)   Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. https://doi.org/10.1002%2F14651858.CD007498.pub3 https://www.cochranelibrary.com Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews T A B L E   O F   C O N T E N T S HEADER......................................................................................................................................................................................................... 1 ABSTRACT..................................................................................................................................................................................................... 2 PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 3 SUMMARY OF FINDINGS.............................................................................................................................................................................. 4 BACKGROUND.............................................................................................................................................................................................. 6 OBJECTIVES.................................................................................................................................................................................................. 6 METHODS..................................................................................................................................................................................................... 6 RESULTS........................................................................................................................................................................................................ 8 Figure 1.................................................................................................................................................................................................. 9 Figure 2.................................................................................................................................................................................................. 10 Figure 3.................................................................................................................................................................................................. 11 Figure 4.................................................................................................................................................................................................. 13 Figure 5.................................................................................................................................................................................................. 14 Figure 6.................................................................................................................................................................................................. 15 DISCUSSION.................................................................................................................................................................................................. 16 AUTHORS' CONCLUSIONS........................................................................................................................................................................... 17 ACKNOWLEDGEMENTS................................................................................................................................................................................ 18 REFERENCES................................................................................................................................................................................................ 19 CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 24 DATA AND ANALYSES.................................................................................................................................................................................... 72 Analysis 1.1. Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 1 Mortality at 30 days.............................................................................................................................................................................. 72 Analysis 1.2. Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 2 Treatment failure at 30 days................................................................................................................................................................ 74 Analysis 2.1. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 1 Mortality at 30 days stratified by adherence...................................................................................................................................................... 76 Analysis 2.2. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 2 Treatment failure at 30 days stratified by adherence......................................................................................................................... 77 Analysis 2.3. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 3 Mortality at 30 days stratified by allocation concealment................................................................................................................................. 78 Analysis 2.4. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 4 Treatment failure at 30 days stratified by allocation concealment................................................................................................... 80 Analysis 2.5. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 5 Mortality at 30 days stratified by blinded outcome assessment....................................................................................................................... 81 Analysis 2.6. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 6 Treatment failure at 30 days stratified by blinded outcome assessment......................................................................................... 82 Analysis 2.7. Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 7 Mortality at 30 days stratified by follow up........................................................................................................................................................ 83 ADDITIONAL TABLES.................................................................................................................................................................................... 85 APPENDICES................................................................................................................................................................................................. 97 FEEDBACK..................................................................................................................................................................................................... 98 WHAT'S NEW................................................................................................................................................................................................. 99 HISTORY........................................................................................................................................................................................................ 99 CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 100 DECLARATIONS OF INTEREST..................................................................................................................................................................... 100 SOURCES OF SUPPORT............................................................................................................................................................................... 101 DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 101 INDEX TERMS............................................................................................................................................................................................... 102 Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. i Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews [Intervention Review] Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections Philipp Schuetz1,2,3, Yannick Wirz1, Ramon Sager1, Mirjam Christ-Crain4, Daiana Stolz5, Michael Tamm5, Lila Bouadma6, Charles E Luyt7, Michel Wol&8, Jean Chastre9, Florence Tubach10, Kristina B Kristo&ersen11, Olaf Burkhardt12, Tobias Welte12,13, Stefan Schroeder14, Vandack Nobre15, Long Wei16, Heiner C C Bucher17,18, Neera Bhatnagar19, Djillali Annane20, Konrad Reinhart21, Angela Branche22, Pierre Damas23, Maarten Nijsten24, Dylan W de Lange25, Rodrigo O Deliberato26, Stella SS Lima27, Vera Maravić-Stojković28, Alessia Verduri29, Bin Cao30, Yahya Shehabi31,32, Albertus Beishuizen33, Jens-Ulrik S Jensen34,35, Caspar Corti34, Jos A Van Oers36, Ann R Falsey22, Evelien de Jong37, Carolina F Oliveira38, Bianca Beghe39, Matthias Briel3,17, Beat Mueller1,2,3 1Medical University Department, Kantonsspital Aarau, Aarau, Switzerland. 2Department of Endocrinology/Metabolism/Clinical Nutrition, Department of Internal Medicine, Kantonsspital Aarau, Aarau, Switzerland. 3Medical Faculty, University of Basel, Basel, Switzerland. 4Clinic for Endocrinology, Diabetes and Metabolism, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 5Clinic of Pneumology and Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland. 6Service de Réanimation Médicale, Hôpital Bichat-Claude Bernard, Université Paris 7-Denis-Diderot, Paris, France. 7Service de Réanimation Médicale, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Paris 6-Pierre-et-Marie-Curie, Paris, France. 8Service de Réanimation Médicale, Université Paris 7-Denis-Diderot, Paris, France. 9Service de Réanimation Médicale, Université Paris 6-Pierre-et-Marie-Curie, Paris, France. 10Département Biostatistique, Santé Publique et Information Médicale, AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, INSERM CIC-P 1421, Sorbonne Universités, UPMC Univ Paris 06, Paris, France. 11Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark. 12Department of Pulmonary Medicine, Medizinische Hochschule Hannover, Hannover, Germany. 13German Center for Lung Reearch (DZL), Gießen, Germany. 14Department of Anesthesiology and Intensive Care Medicine, Krankenhaus Dueren, Dueren, Germany. 15Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais, Minas Gerais, Brazil. 16Department of Internal and Geriatric Medicine, Shanghai Jiao Tong University A&iliated Sixth People's Hospital (East campus), Shanghai, China. 17Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland. 18Medical Faculty, University Hospital Basel, Basel, Switzerland. 19Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada. 20Department of Critical Care, Hyperbaric Medicine and Home Respiratory Unit, Center for Neuromuscular Diseases; Raymond Poincaré Hospital (AP-HP), Garches, France. 21Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany. 22Department of Medicine, Division of Infectious Diseases, University of Rochester School of Medicine, Rochester, NY, USA. 23Department of General Intensive Care, University Hospital of Liege, Domaine universitaire de Liège, Liege, Belgium. 24University Medical Centre, University of Groningen, Groningen, Netherlands. 25Department of Intensive Care, University Medical Center Utrecht, Utrecht, Netherlands. 26Critical Care Unit, Hospital Israelita Albert Einstein, São Paulo, Brazil. 27Graduate Program in Infectious Diseases and Tropical Medicine, Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. 28Immunology Laboratory, Dedinje Cardiovascular Institute, Belgrade, Serbia. 29Department of Medical and Surgical Sciences, Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy. 30Center for Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, National Clinical Research Center of Respiratory Diseases, Capital Medical University, Beijing, China. 31Critical Care and Peri-operative Medicine, Monash Health, Melbourne, Australia. 32School of Clinical Sciences, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne, Australia. 33Department of Intensive Care, Medisch Spectrum Twente, Enschede, Netherlands. 34Department of Respiratory Medicine, Copenhagen University Hospital, Bispebjerg og Frederiksberg, Copenhagen NV, Denmark. 35CHIP, Department of Infectious Diseases and Rheumatology, Finsencentret, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 36Intensive Care Unit, Elisabeth Tweesteden Ziekenhuis, Tilburg, Netherlands. 37Department of Intensive Care, VU University Medical Center, Amsterdam, Netherlands. 38Department of Internal Medicine, School of Medcine, Federal University of Minas Gerais, Belo Horizonte, Brazil. 39Department of Medical and Surgical Sciences, AOU Policlinico di Modena, Moderna, Italy Contact address: Philipp Schuetz, Medical University Department, Kantonsspital Aarau, Aarau, Switzerland. schuetzph@gmail.com. Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: Edited (no change to conclusions), comment added to review, published in Issue 5, 2019. Citation: Schuetz P, Wirz Y, Sager R, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wol& M, Chastre J, Tubach F, Kristo&ersen KB, Burkhardt O, Welte T, Schroeder S, Nobre V, Wei L, Bucher HCC, Bhatnagar N, Annane D, Reinhart K, Branche A, Damas P, Nijsten M, de Lange DW, Deliberato RO, Lima SSS, Maravić-Stojković V, Verduri A, Cao B, Shehabi Y, Beishuizen A, Jensen JUS, Corti C, Van Oers JA, Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 mailto:schuetzph@gmail.com Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Falsey AR, de Jong E, Oliveira CF, Beghe B, Briel M, Mueller B. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database of Systematic Reviews 2017, Issue 10. Art. No.: CD007498. DOI: 10.1002/14651858.CD007498.pub3. Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. A B S T R A C T Background Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT-guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in di&erent patient populations with ARIs and di&erent settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the e&ect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta-analysis first published in 2012 designed to look at the safety of PCT-guided antibiotic stewardship. Objectives The aim of this systematic review based on individual participant data was to assess the safety and e&icacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from di&erent clinical settings. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017. Selection criteria We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT- guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment. Data collection and analysis Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all-cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic-related side e&ects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed-e&ect model. The di&erent trials were added as random-e&ects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta-analysis. Main results 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 e&ects. 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 e&ect 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 e&ects (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. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 https://doi.org/10.1002%2F14651858.CD007498.pub3 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Authors' conclusions 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 e&ects. Results were similar for di&erent 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. P L A I N   L A N G U A G E   S U M M A R Y Testing blood procalcitonin levels to decide when to start and stop antibiotics in adults with acute respiratory tract infections Review question What are the e&ects of using procalcitonin to start or discontinue antibiotics in people with acute respiratory infections compared to routine care on mortality and treatment failure? Background In people with acute respiratory infections, unnecessary antibiotic use significantly contributes to increasing bacterial resistance, medical costs, and the risk of drug-related adverse events. The blood marker procalcitonin increases in bacterial infections and decreases when patients recover from the infection. Procalcitonin can be measured in the blood of patients by di&erent commercially available assays with a turnaround time of around one to two hours and support clinical decision making about initiation and discontinuation of antibiotic therapy. Search date We conducted electronic searches on 10 February 2017. We conducted searches for ongoing trials on 12 April 2017. Study characteristics 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. Study funding sources 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). Key results 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 di&erence with regard to treatment failures. Results were similar for di&erent 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 e&ects (16.3% versus 22.1%). Quality of the evidence 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 e&ects because the definitions for these endpoints among trials were not identical. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 P ro ca lcito n in to in itia te o r d isco n tin u e a n tib io tics in a cu te re sp ira to ry tra ct in fe ctio n s (R e v ie w ) C o p yrig h t © 2019 T h e C o ch ra n e C o lla b o ra tio n . P u b lish ed b y Jo h n W ile y & S o n s, Ltd . 4 S U M M A R Y   O F   F I N D I N G S   Summary of findings for the main comparison.   Procalcitonin algorithm compared to standard care for guiding antibiotic therapy in acute respiratory tract infections Procalcitonin algorithm compared to standard care for guiding antibiotic therapy in acute respiratory tract infections Patient or population: people with acute respiratory tract infections Settings: primary care, emergency department, intensive care unit Intervention: PCT-guided care Comparison: standard care Illustrative comparative risks* (95% CI) Assumed risk Corresponding risk Outcomes Standard care PCTalgorithm Relative effect (95% CI) No. of partici- pants (studies) Quality of the evidence (GRADE) Comments Study populationMortality Follow-up: 30 days 100 per 1000 86 per 1000 (76 to 95) OR 0.83 (0.70 to 0.99) 6708 (26 studies) ⊕⊕⊕⊕ High1   Study populationTreatment failure Clinical assessment3 Follow-up: 30 days 249 per 1000 230 per 1000 (216 to 245) OR 0.90 (0.80 to 1.01) 6708 (26 studies) ⊕⊕⊕⊝ Moderate2 3   Antibiotic-related side effects Follow-up: 30 days Study population 221 per 1000 163 per 1000 (145 to 182) OR 0.68 (0.57 to 0.82) 3034 (6 studies) ⊕⊕⊕⊝ Moderate4   Antibiotic exposure Total days of antibiotic therapy in all randomised participants The mean antibiotic ex- posure in the control groups was 8.1 days. The mean antibiotic exposure in the intervention groups was 2.43 dayslower (2.15 to 2.71) - 6708 (26 studies) ⊕⊕⊕⊕ High1   *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OR: odds ratio: PCT: procalcitonin GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. C o ch ra n e L ib ra ry T ru ste d e v id e n ce . In fo rm e d d e cisio n s. B e tte r h e a lth .    C o ch ra n e D a ta b a se o f S ystem a tic R e vie w s P ro ca lcito n in to in itia te o r d isco n tin u e a n tib io tics in a cu te re sp ira to ry tra ct in fe ctio n s (R e v ie w ) C o p yrig h t © 2019 T h e C o ch ra n e C o lla b o ra tio n . P u b lish ed b y Jo h n W ile y & S o n s, Ltd . 5 Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1No downgrading for serious concerns. Still, there is some concern about unconcealed allocation in several trials in the emergency department and intensive care settings. There is also some concern about low adherence with the PCT algorithm in the intervention group. We consider unblinded outcome assessment as not relevant for the outcome of death. 2Downgraded one level for serious inconsistency: trials used di&ering definition of treatment failure and some rare events were not systematically assessed among trials. 3For the primary care setting, treatment failure was defined as death, hospitalisation, acute respiratory infection (ARI)-specific complications (e.g. empyema for lower ARI, meningitis for upper ARI), recurrent or worsening infection, and participants reporting any symptoms of an ongoing respiratory infection (e.g. fever, cough, dyspnoea) at follow- up. For the emergency department setting, treatment failure was defined as death, intensive care unit (ICU) admission, rehospitalisation a[er index hospital discharge, ARI- associated complications (e.g. empyema or acute respiratory distress syndrome for lower ARI), and recurrent or worsening infection within 30 days of follow-up. For the ICU setting, treatment failure was defined as death within 30 days of follow-up. 4Downgraded one level for incomplete reporting: only 6 trials reported side e&ects from antibiotics, and none of these trials were conducted in the ICU setting.   C o ch ra n e L ib ra ry T ru ste d e v id e n ce . In fo rm e d d e cisio n s. B e tte r h e a lth .    C o ch ra n e D a ta b a se o f S ystem a tic R e vie w s Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews B A C K G R O U N D Acute respiratory infections (ARIs) account for over 10% of global disease burden and are the most common reason for antibiotic therapy in primary care and hospital settings (Evans 2002; Gonzales 1997; Zaas 2014). Description of the condition Acute respiratory infections comprise a heterogeneous group of infections including bacterial, viral, and other aetiologies. As many as 75% of all antibiotic doses are prescribed for ARIs, despite their mainly viral cause (Doan 2014; Evans 2002). Early initiation of adequate antibiotic therapy is the cornerstone in the treatment of bacterial ARIs and is associated with improved clinical outcomes (Hoare 2006; Kumar 2006; Kumar 2009; Liberati 2009b; Spurling 2010). However, overuse of antibiotics by overprescription in outpatients with bronchitis (Arnold 2005), for instance, and prolonged duration of antibiotic therapy in people with bacterial ARIs in the hospital and intensive care unit (ICU) settings is associated with increased resistance to common bacteria, high costs, and adverse drug reactions (Gonzales 1997; Goossens 2005; Lawrence 2009; Zaas 2014). Description of the intervention The presence of a diagnostic 'gold standard' or reference standard represents the best available method for establishing the presence or absence of a disease. Optimally, a morphological verification such as histopathology or, in the case of ARIs, growth of typical pathogens in blood cultures or sputum cultures can be obtained to establish the 'correct' diagnosis. Regrettably, the use of blood cultures as the assumed gold standard in ARIs lacks sensitivity, specificity, or both, with only around 10% of people with pneumonia having positive cultures and some of them being false positives (Muller 2010). In this diagnostic uncertainty, surrogate biomarker to estimate the likelihood for the presence of a bacterial infection and to grade disease severity are of great interest (Schuetz 2015). In such a circumstance, two fundamentally di&erent concepts are employed. One concept tends to ignore potential dilemmas in the accuracy of the alleged gold standard but assumes a well-defined illness, which is represented by the assumption drawn following a diagnostic test or a clinical diagnosis. The second concept discards alleged gold standards and focuses on patient outcomes. In the case of ARIs, the clinical benefit of a diagnostic biomarker, such as procalcitonin (PCT), can be measured by clinical outcomes of randomised intervention studies, assuming that if the person recovered without antibiotics then there was no relevant bacterial illness. In recent years, PCT has emerged as a promising marker for the diagnosis of bacterial infections because higher levels are found in severe bacterial infections but remain fairly low in viral infections and non-specific inflammatory diseases (Muller 2000; Muller 2001; Muller 2010). Procalcitonin is released in multiple tissues in response to bacterial infections via a direct stimulation of cytokines, such as interleukin (IL)-1β, tumour necrosis factor (TNF)- ɑ, and IL-6. Conversely, PCT production is blocked by interferon gamma, a cytokine released in response to viral infections (Muller 2000). Hence, PCT may be used to support clinical decision making for the initiation and discontinuation of antibiotic therapy in di&erent types of infections and indications (Sager 2017; Schuetz 2016). Randomised controlled trials (RCTs) have demonstrated the feasibility of such a strategy in di&erent ARI patient populations and di&erent settings ranging from primary care to emergency departments and hospital wards to medical and surgical ICUs (Bloos 2016; Branche 2015; Corti 2016; De Jong 2016; Deliberato 2013; Layios 2012; Long 2014; Maravić-Stojković 2011; Oliveira 2013; Shehabi 2014; Verduri 2015; Wang 2016). How the intervention might work Procalcitonin levels correlate with the risk of relevant bacterial infections and decrease upon recovery. Procalcitonin testing may therefore help physicians decide in which patients antibiotics are needed and when it is safe to stop treatment (Kutz 2015). The use of PCT in clinical protocols may thus decrease antibiotic consumption in two ways: by preventing unnecessary antibiotic prescriptions and by limiting durations of antibiotic treatment (Sager 2017; Schuetz 2011a). Why it is important to do this review While several RCTs have evaluated PCT-guided antibiotic treatment, most individual trials included participants with di&erent types of respiratory and non-respiratory infections and lacked the statistical power to assess the risk for mortality and severe infectious disease complications associated with PCT-guided decision making. Previous meta-analyses of RCTs investigating the e&ect of PCT algorithms on antibiotic use focused on  the critical care setting, people with suspicion of bacterial infections, and people with sepsis and respiratory infections (Heyland 2011; Hoeboer 2015; Tang 2009; Wacker 2013). However, these meta-analyses used aggregated data and were not able to investigate the e&ects of PCT on di&erent ARI diagnoses and on outcomes other than mortality. A previous meta-analysis based on individual participant data published in the Cochrane Library did not find a significant di&erence in clinical outcomes, but confidence intervals remained relatively wide (Schuetz 2012). Safety of using PCT for antibiotic decision making remained thus unproven. O B J E C T I V E S The aim of this systematic review based on individual participant data was to assess the safety and e&icacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from di&erent clinical settings. M E T H O D S Criteria for considering studies for this review Types of studies Prospective RCTs comparing a strategy to initiate or discontinue antibiotic therapy based on PCT levels with a control arm without PCT measurements were eligible for inclusion. Participants were randomised to receive antibiotics either based on PCT levels ('PCT- guided' group) or a control group without knowledge of PCT levels, including antibiotic management based on usual care or guidelines. We did not include non-randomised studies. Types of participants We included adult participants with clinical diagnoses of ARIs: either a lower ARI including community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), acute bronchitis, exacerbation of asthma, or Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews exacerbation of chronic obstructive pulmonary disease (COPD); or an upper ARI including common cold, rhino-sinusitis, pharyngitis, tonsillitis, or otitis media. We also included people with sepsis and suspected ARIs in the analyses. We excluded trials if they focused exclusively on children or used PCT to escalate antibiotic therapy. We made no exclusions based on language of reports or clinical setting. We included trials from primary care, emergency departments, and medical and surgical ICUs. Types of interventions Strategies to initiate or discontinue antibiotic therapy based on PCT levels compared with usual care were eligible. Types of outcome measures We defined primary and secondary outcomes to a follow-up time of 30 days. For trials with shorter follow-up periods, we used the available information (i.e. until hospital discharge). We excluded all trials with di&erent follow-up times for mortality in a sensitivity analysis. Primary outcomes 1. All-cause mortality following randomisation up to a follow-up time of 30 days. 2. Setting-specific treatment failure within 30 days of inclusion. For the primary care setting, we defined treatment failure as death, hospitalisation, ARI-specific complications (e.g. empyema for lower ARIs, meningitis for upper ARIs), recurrent or worsening infection, and still having ARI-associated discomfort at 30 days. For the emergency department setting, we defined treatment failure as death, ICU admission, rehospitalisation a[er index hospital discharge, ARI-associated complications (e.g. empyema or acute respiratory distress syndrome for lower ARIs), and recurrent or worsening infection within 30 days of follow-up. For the medical and surgical ICU setting, we defined treatment failure as death within 30 days of follow-up and recurrent or worsening infection. Secondary outcomes 1. Antibiotic use (initiation of antibiotics, duration of antibiotics, and total exposure to antibiotics (total amount of antibiotic days divided by total number of participants)). 2. Length of hospital stay for hospitalised participants. 3. Length of ICU stay for critically ill participants. 4. Number of days with restricted activities within 14 days a[er randomisation for primary care participants. 5. Antibiotic-related side e&ects. Search methods for identification of studies We updated the search strategy for this review in February 2017 in collaboration with the Cochrane Acute Respiratory Infections Group's Information Specialist. We performed data collection based on the protocol of a previous meta-analysis of individual participant data published in the Cochrane Library (Schuetz 2008). Electronic searches We updated the searches for this review in February 2017, running the search across all databases from the date of inception to 10 February 2017. We screened all new references identified by the search. We searched the following databases for published studies: • The Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1), part of the Cochrane Library, which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, www.cochranelibrary.com/ (accessed 10 February 2017) (Appendix 1); • MEDLINE Ovid (1966 to 10 February 2017) (Appendix 2); • Embase.com (1980 to 10 February 2017) (Appendix 3). We used the search strategy in Appendix 4 to conduct searches for the 2012 version of this review (Schuetz 2012). We also searched for ongoing and completed trials in the following trial register: • US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov/; searched 12 April 2017). We did not apply any language or publication restrictions. Searching other resources We contacted experts for further eligible trials. Data collection and analysis We requested individual participant data from the investigators of all included trials. We checked all provided data against published reports, and if needed, corrected any discrepancies. We prepared this review update according to PRISMA guidelines and the PRISMA-IPD guideline (Liberati 2009a; Stewart 2015). Selection of studies At least two review authors (RS, YW, PS) independently assessed trial eligibility based on titles, abstracts, full-text reports, and further information from investigators as needed. Data extraction and management We checked data from each trial against reported results and resolved any queries with the principal investigator, trial data manager, or statistician. The mortality and adverse outcome rates from trials included in this review may di&er slightly from previous reports because we treated data in a consistent manner across all trials. Assessment of risk of bias in included studies Two review authors (RS, YW) assessed the methodological quality of each included study using the Cochrane 'Risk of bias' tool and resolved any disagreements by discussion (Higgins 2011). Methodological criteria included: adequate sequence generation and concealment of treatment allocation; blinding of participants, physicians and clinical outcome assessment; whether the study was free of selective reporting; and the proportion of participants lost to follow-up. We documented the proportion of participants in the PCT group that adhered to the PCT algorithm used in each study, defining adherence to the PCT algorithm of lower than 70% as high risk of bias, and, if not reported, as unclear risk. Due to the study design of the included studies, physicians were aware of the participants' study group because in the intervention group physicians used the PCT result for decision making about antibiotic treatment, while in the control group  no PCT result was communicated to the physicians. Blinding of physicians was Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 http://www.cochranelibrary.com/ https://www.clinicaltrials.gov/ Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews therefore not feasible, resulting in an unclear risk for performance bias in all studies. We assessed the quality of evidence at the outcome level using the GRADE approach (GRADEpro GDT 2014). Measures of treatment e>ect We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression for the co-primary endpoints of mortality from any cause and treatment failure (Thompson 2001; Turner 2000). We fitted corresponding linear and logistic regression models for continuous and binary secondary endpoints, respectively. We calculated Kaplan-Meier curves for time to death for graphical display. We used Stata version 12.1 (College Station, TX) for statistical analyses (Stata 12.1). Unit of analysis issues The unit of our primary analysis was the individual study participant. We analysed all participants in the study group to which they were randomised. We calculated summary estimates using aggregated data from individual trials as a sensitivity analysis. Dealing with missing data We received the full data sets from all trials included in the individual participant data analysis (n = 26) with all available follow- up information (if recorded in the trials). We assumed in our main analysis that participants lost to follow- up did not experience an event. We explored if a complete-case analysis (excluding participants lost to follow-up) or an analysis assuming that participants lost to follow-up experienced an event would change the results for the primary outcomes of mortality and treatment failure in sensitivity analyses. We checked all individual participant data against the published results but did not find significant di&erences that warranted further exploration. Assessment of heterogeneity We performed prespecified analyses stratified by clinical setting (i.e. primary care, emergency department, ICU) and ARI diagnosis (CAP, COPD, bronchitis, VAP) to investigate the consistency of results across our heterogeneous patient populations in terms of disease severity. We formally tested for potential subgroup e&ects by adding the clinical setting and ARI diagnosis in turn to the regression model together with the corresponding interaction term with the PCT group as a fixed-e&ect model. We assessed heterogeneity by estimating the I2 statistic (the percentage of total variance across trials that is due to heterogeneity rather than chance) in meta-analyses using aggregated data and by testing for heterogeneity using the Cochran Q test (Higgins 2003). Assessment of reporting biases We assessed reporting bias by attempting to identify if the study was included in a trial registry, a protocol was available, and if the methods section provided a list of outcomes. We compared listed outcomes from those sources to outcomes reported in the published papers. Data synthesis We used multivariable hierarchical logistic regression to combine participant data from the trials (Thompson 2001; Turner 2000). Apart from the group variable indicating the use of a PCT algorithm, we included important prognostic factors such as participant age and ARI diagnosis as an additional fixed e&ect; to account for within- and between-trial variability, we added a categorical trial variable to the model as a random e&ect. In meta-analyses with aggregated trial data we calculated summary ORs using a random- e&ects model and the Mantel-Haenszel facility of Review Manager 5 (RevMan 2014). GRADE and 'Summary of findings' table We created a 'Summary of findings' table using the following outcomes: all-cause mortality at 30 days, setting-specific treatment failure at 30 days, total exposure to antibiotics, and antibiotic- related side e&ects (Summary of findings for the main comparison). The results reported in this table correspond to the main IPD analysis and are slightly di&erent from the aggregate data analysis. We used the five GRADE considerations (study limitations, consistency of e&ect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta-analyses for the prespecified outcomes (Atkins 2004). We used the methods and recommendations in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), employing GRADEpro GDT so[ware (GRADEpro GDT 2014). We justified all decisions to down- or upgrade the quality of studies using footnotes, and we made comments to aid the reader's understanding of the review where necessary. Subgroup analysis and investigation of heterogeneity We performed prespecified analyses stratified by clinical setting and ARI diagnosis and formally tested for potential subgroup e&ects by adding an interaction term into the statistical model. Sensitivity analysis We performed prespecified sensitivity analyses based on the main quality indicators: allocation concealment, blinded outcome assessment, adherence to the PCT algorithm (we defined low adherence to PCT algorithms as < 70%), and follow-up time for mortality other than one month. We also performed an aggregate data meta-analysis using all trials with potentially eligible participants. R E S U L T S Description of studies See: Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies tables. Results of the search A[er removal of duplicates, we identified 998 records that we further assessed based on title and abstracts, excluding 919 records. We obtained 79 full-text study reports, and following assessment excluded 39 that did not meet our inclusion criteria. Eight studies were ongoing trials. From 32 eligible RCTs (9909 participants) including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which were included in the main individual Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews participant data meta-analysis (see Figure 1). We did not obtain individual participant data for four trials, and two trials did not include participants with confirmed ARIs. The sensitivity aggregate analysis includes all 32 trials.   Figure 1.   Study flow diagram. Abbreviations: ARI: acute respiratory infection; IPD: individual participant data; RCT: randomised controlled trial   Included studies We included a total of 26 studies involving 6708 participants in the main individual participant data meta-analysis. Study characteristics are presented in Table 1. Participants Baseline characteristics of included participants were similar in the PCT and control groups with respect to important prognostic features (Table 2). Most participants were recruited either in the emergency department or ICU setting, and CAP was the most frequent ARI diagnosis, reported in more than 40% of participants. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Settings Trials were conducted in 12 countries: Switzerland, Germany, France, Italy, USA, China, Denmark, Netherlands, Brazil, Belgium, Australia, and Serbia. Trials were conducted in di&erent clinical settings including primary care, emergency departments and medical wards, and ICU. There were two primary care trials with upper and lower respiratory infection patients; 11 emergency department and medical ward trials with lower ARI patients; and 13 ICU trials with mostly septic patients due to infections of the lower respiratory tract. Interventions Procalcitonin algorithms used in the di&erent trials were similar in concept and recommended initiation and/or continuation of antibiotic therapy based on similar PCT cut-o& levels (reviewed in Schuetz 2011a). However, there were di&erences: some trials in primary care and the emergency department used only a single PCT measurement on admission to guide initiation of antibiotics, while the other trials (predominantly in hospitalised patients with severe infections) used repeated measurements for guiding the duration of treatment. One trial used a point-of-care device (Corti 2016). Adherence to algorithms varied, ranging from 44% to 100% (Table 3). Comparators In control group participants, PCT was not used to guide treatment decisions, but this decision was up to the treating physician team. In some trials, physicians were asked to follow antibiotic guidelines for control group participants (Briel 2008; Schuetz 2009). In one trial, the control group was guided with C-reactive protein levels (Oliveira 2013). Funding sources All studies were investigator-initiated trials. Half of the trials were funded by national agencies or did not report funding; the other half of the trials received funding from the biomarker industry (e.g. Thermo Fisher Scientific). Excluded studies We excluded a total of 39 studies due to wrong intervention (n = 1), wrong population (n = 2), and wrong design (not RCT) (n = 36). A total of nine studies reported as ongoing in the 2012 review were now available for assessment; we included four of these studies in this current update (Annane 2013; Bloos 2016; De Jong 2016; Lima 2016), and did not include five studies due to wrong population (paediatrics). Ongoing studies Our searches of the trial register identified seven ongoing studies that we will assess for inclusion for the next review update (Ongoing studies). These studies focus on the utility of PCT in people with pneumonitis (NCT02862314), pulmonary embolism (NCT02261610), lower respiratory infection (NCT02130986), heart failure (NCT02787603), and intraoperative positive-end expiratory pressure optimisation (NCT02931409). Two trials are antibiotic e&icacy trials (NCT02332577; NCT02440828). Risk of bias in included studies The overall risk of bias is presented graphically in Figure 2 and Figure 3. The risk of bias was mostly low for random sequence generation, allocation concealment, incomplete outcome data, and selective reporting; unclear for blinding of personnel in all studies; and mostly high for blinding of outcome assessment.   Figure 2.   'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.     Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Figure 3.   'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.     Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Figure 3.   (Continued)   Allocation All studies randomised participants to intervention (PCT testing) or control groups. A total of 25 trials with mainly computer- generated lists and centralised randomisation were at low risk of selection bias. Seven trials were at high or unclear risk of selection bias. Risk for selection bias with regard to random sequence generation was due to weekly allocation (Christ-Crain 2004), unnumbered envelopes (Christ-Crain 2006; Stolz 2007), use of odd and even patient identification numbers (Long 2009; Long 2011), and unconcealed drawing of lots (Hochreiter 2009; Schroeder 2009). Blinding None of the included trials blinded physicians to group allocation because PCT was used for decision making in the intervention group, thus all trials had unclear risk for blinding of participants and personnel. All trials used blinded outcome assessment (Briel 2008; Bouadma 2010; Branche 2015; Layios 2012; Schuetz 2009; Shehabi 2014; Stolz 2007; Tang 2013), employing blinded telephone interviews to assess vital status and other outcomes. Incomplete outcome data The included trials had a high follow-up for mortality with few participants lost to follow-up (Table 3). In seven trials, outcome assessment was done a[er hospital or ICU discharge (Deliberato 2013; Hochreiter 2009; Kristo&ersen 2009; Layios 2012; Long 2009; Schroeder 2009; Shehabi 2014). One trial had a high number of post randomisation exclusions (six in the intervention arm versus four in the control group) and thus had an unclear risk of bias (Ding 2013). Selective reporting No reporting bias was found when study protocols and final results were compared. However, we did not find registration numbers for four trials (Ding 2013; Layios 2012; Maravić-Stojković 2011; Najafi 2015), which we considered to be at unclear risk of bias. We found no evidence of reporting bias by visual inspection of funnel plots (Figure 4).   Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Figure 4.   Funnel plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.   Other potential sources of bias Another potential source of bias relates to low adherence to the PCT algorithms, particularly for safety endpoints. Overall, adherence varied, ranging from 44% to 100% (Table 3). With regard to funding, 16 trials reported no industry funding (six did not report any funding, 10 reported public funding), and in 16 trials Thermo Fisher, the producer of the PCT assay, funded or co funded the studies by providing free-of-charge PCT kits or additional research funds, or both. E>ects of interventions See: Summary of findings for the main comparison Procalcitonin algorithm compared to standard care for guiding antibiotic therapy in acute respiratory tract infections Primary outcomes 1. All-cause mortality following randomisation up to a follow-up time of 30 days There were 286 deaths in 3336 PCT-guided participants (8.6%) compared to 336 in 3372 controls (10.0%) resulting in a significantly lower mortality associated with PCT-guided therapy (adjusted odds ratio (OR) 0.83, 95% confidence interval (CI) 0.70 to 0.99, P = 0.037) (Table 4). This e&ect was consistent across clinical settings (P for interaction > 0.05), although mortality could not be estimated in primary care trials because only one death was reported in a control group participant. The e&ect on mortality was also consistent among di&erent ARI diagnoses (CAP, COPD, bronchitis, VAP) (P for interaction > 0.05). As a further sensitivity analysis and to investigate heterogeneity among trials, we also calculated an aggregate data meta-analysis based on the aggregate results of all 32 potentially eligible trials (thus not limited to ARI participants only). In this analysis, the results proved robust, although the mortality estimate did not reach statistical significance (OR 0.89, 95% CI 0.78 to 1.01; Analysis 1.1; Figure 5). There was no evidence of heterogeneity (I2 = 0%).   Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Figure 5.   Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.   2. Setting-specific treatment failure within 30 days of inclusion Treatment failure was not significantly lower in PCT-guided participants (23.0% versus 24.9%, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). These results were similar among subgroups by clinical setting and type of respiratory infection (P for interaction > 0.05). With an OR of 0.90 (95% CI 0.81 to 0.99), treatment failure was significantly lower in PCT group participants in an aggregate data meta-analysis based on all 32 potentially eligible trials (thus relying on the original definition of treatment failure as used in the trials). There was no evidence of heterogeneity (I2 = 0%) (Figure 6). We also performed several predefined sensitivity analyses, which showed no evidence for interactions (see summary in Table 5).   Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Figure 6.   Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.2 Treatment failure at 30 days.   Secondary outcomes 1. Antibiotic use (initiation of antibiotics, duration of antibiotics, and total exposure to antibiotics (total amount of antibiotic days divided by total number of participants)) Procalcitonin guidance was associated with a reduction in total antibiotic exposure (mean 8.1 days compared to 5.7 days, regression coe&icient -2.43 days (95% CI -2.71 to -2.15), P < 0.001). Also, duration of antibiotic treatment in treated participants was shorter (mean 9.4 days compared to 8.0 days, adjusted coe&icient -1.83 days (95% CI -2.15 to -1.5), P < 0.001) (Table 6). 2. Length of hospital stay for hospitalised participants However, the e&ect on antibiotic consumption di&ered according to clinical setting. In the primary care setting, lower antibiotic exposure was mainly due to lower initial prescription rates (P < 0.001 for interaction between primary care setting and PCT group on antibiotic prescriptions). Similarly, lower antibiotic exposure due to lower prescription rates was found in selected infections such as acute bronchitis (adjusted OR 0.18, 95% CI 0.12 to 0.26; P for interaction < 0.001). Lower antibiotic prescription rates (adjusted OR 0.49, 95% CI 0.41 to 0.58) and shorter duration of antibiotic therapy in participants with initiation of antibiotic Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews (adjusted coe&icient -2.45 days, 95% CI -2.86 to -2.05) contributed to the lower overall exposure in the emergency department setting. Length of hospital stay and ICU stay were similar in both groups with no evidence for di&erent e&ects in subgroups (P for interaction > 0.05). 3. Length of ICU stay for critically ill participants For the ICU setting, the lower exposure was mainly explained by shorter treatment durations (adjusted di&erence in days -1.23, 95% CI -1.82 to -0.65). Similarly, for CAP, the lower exposure was mainly explained by shorter durations (adjusted di&erence in days -2.45, 95% CI -2.87 to -2.02). 4. Number of days with restricted activities within 14 days a1er randomisation for primary care participants For studies conducted in the primary care setting, there was no di&erence in days with restricted activities of daily living between PCT and control group participants (days, 8.9 ± 4.2 versus 8.9 ± 4.1, regression coe&icient 0.07 (95% CI -0.44 to 0.59), P = 0.777). 5. Antibiotic-related side e3ects There was also a significant reduction in antibiotic-related side e&ects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). This outcome was only assessed in some of the primary care and emergency department trials (n = 6), and not in ICU trials. There was no evidence for subgroup e&ects (P for interaction > 0.05). D I S C U S S I O N Summary of main results This updated systematic review and meta-analysis included 32 trials, of which 26 trials were used for the main individual participant data analysis. Trials were conducted in 12 countries and included di&erent clinical settings and types of respiratory infections. There was mostly low risk for random sequence generation, allocation concealment, incomplete outcome data, and selective reporting. There was unclear risk in all studies for blinding of personnel, and mostly high risk for blinding of outcome assessment. The results indicate a significant reduction in mortality (high-quality evidence according to GRADE, Summary of findings for the main comparison) and non-significant result for treatment failure (moderate-quality evidence according to GRADE, Summary of findings for the main comparison) when PCT was used to guide initiation and duration of antibiotic treatment in ARI participants compared to control participants. Additionally, antibiotic consumption and side e&ects from antibiotics were significantly reduced across di&erent clinical settings and types of ARIs. There was no e&ect on length of hospital stay and ICU length of stay. Results were similar in subgroup and sensitivity analyses including an aggregate data analysis with all 32 potentially eligible trials. Limitations include incomplete individual participant data, with four research groups not agreeing to the sharing of individual participant data; incomplete follow-up information in some of the trials where no outcome assessment was done a[er 30 days of enrolment; di&erences in definitions of treatment failure among trials; and exclusion of some patient populations such as immunosuppressed people. Still, results from this updated individual participant data meta-analysis support the use of PCT in the context of antibiotic stewardship in people with ARIs. Overall completeness and applicability of evidence The strengths of our review include an explicit study protocol, a comprehensive search to retrieve all relevant trials, access to individual participant-level data from all but four of the included trials, and standardised outcome definitions across trials, thereby overcoming limitations of meta-analyses using aggregated data. To minimise the risk of data-driven associations, we prespecified a limited number of prognostic factors and subgroup variables for our statistical model. We allowed for potential clustering e&ects by using random-e&ects models for included trials. Our results proved robust in sensitivity analyses focusing on high-quality trials and on participants with complete follow-up data. The accuracy of PCT for diagnosing bacterial infections has been called into question by previous meta-analyses of observational studies, which demonstrated mixed results (Jones 2007; Simmonds 2005; Tang 2007; Uzzan 2006). However, a more recent meta- analysis using positive culture as the reference method found moderate to high discrimination of systematic inflammatory response syndrome and sepsis (Wacker 2013). Since there are no available gold standards for the diagnosis of the clinical conditions included in our analysis, most studies used clinical consensus criteria, which may di&er among studies. Rather than relying on these imperfect diagnostic criteria, we were able to assess the value of PCT algorithms by means of RCTs measuring clinically relevant, participant-level outcomes. Despite these merits, this review has several limitations. We limited our analysis to adults with ARIs who were mostly immunocompetent, and excluded some pathogens (i.e. Legionella or Pseudomonas infections). The results of these trials may therefore not be generalised to people who are immunocompromised, with specific pathogens or infections other than ARIs, or children. Previous RCTs have shown that PCT guidance also reduces antibiotic exposure in a neonatal sepsis population but not in children with fever without a source (Manzano 2010). We found several ongoing RCTs in children evaluating PCT algorithms that should shed further light on the benefits and harms of PCT use for children.  The included trials compared the PCT strategy to a control group where antibiotic therapy was guided based on 'usual practice' or based on current guideline recommendations. The magnitude of antibiotic reduction obviously correlates strongly with antibiotic prescription patterns, and in regions of low antibiotic prescription the PCT strategy may have smaller e&ects. Quality of the evidence Characteristics of the individual trials are presented in Table 1. Most trials had a follow-up of one month, with two trials assessing outcome a[er 14 to 21 days and several trials following participants until hospital discharge (or ICU discharge) only. Procalcitonin algorithms used in the di&erent trials were similar in concept and recommended initiation and/or continuation of antibiotic therapy based on similar PCT cut-o& levels (Table 1). However, there were di&erences: some trials in primary care and the emergency department used only a single PCT measurement on admission to guide initiation of antibiotics (Burkhardt 2010; Christ- Crain 2004), while the other trials (predominantly in hospitalised participants with severe infections) used repeated measurements for guiding the duration of treatment. Adherence to algorithms was variable. In terms of methodological quality, trials had concealed allocation, but in several trials blinded outcome assessment was Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 16 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews not done. All trials achieved complete or near-complete follow-up for mortality. None of the trials blinded participants or physicians to group allocation. The overall quality of the evidence according to GRADE was moderate to high (Summary of findings for the main comparison). Potential biases in the review process Due to the di&erences in patient populations included in this analysis, which ranged from primary care to the ICU, we adapted the definition of treatment failure to clinical settings by including setting-specific components in this composite outcome. This may challenge the clinical interpretation in the overall analysis. Agreements and disagreements with other studies or reviews While mortality did not di&er significantly in our initial meta- analysis (adjusted OR 0.94, 95% CI 0.71 to 1.23) (Schuetz 2012), we found a significantly lower mortality rate in PCT-guided participants in this update. This result was robust in subgroup analyses and in our sensitivity analysis. Also, when considering all trials in the aggregate data analysis, mortality tended to be reduced, although not significantly (OR 0.89, 95% CI 0.78 to 1.01). Importantly, the largest-yet ICU trial from the Netherlands has reported a significantly lower mortality in PCT-guided participants (De Jong 2016). Two of the included individual trials reported reduced length of stay, particularly within the ICU. Yet, despite a marked reduction in the duration of antibiotic therapy across trials and settings, there was no di&erence in length of ICU and hospital stay between the two groups in our comprehensive analysis. One might expect that clinically stable patients with discontinued intravenous antibiotics could be safely discharged unless there are extenuating circumstances. Perceived needs by physicians to further monitor these patients in the unit or inability to transfer patients to other inpatient or a[ercare locations may partly explain this finding. There is ongoing controversy about the diagnostic performance of PCT and other blood markers to correctly identify patients with a bacterial infection. In fact, several observational studies have questioned the added value of PCT in addition to clinical signs, such as a primary care study authored by van Vugt and colleagues reporting no additional benefit of PCT to a clinical assessment (van Vugt 2013). Importantly, in the context of respiratory infections, diagnostic studies are limited by the lack of a reference standard, with blood cultures only detecting a minority of cases (e.g. only 10% to 20% of patients with clinically and radiologically confirmed CAP have positive blood cultures) (Muller 2010; Wacker 2013). Interventional research, such as the trials included in the current analysis, do not rely on a reference standard but compare resource use (e.g. antibiotics) and clinical outcomes in people with and without use of the diagnostic marker. For the primary care setting, PCT had a very strong e&ect on antibiotic consumption (reduction of antibiotic exposure by 70%, from 4.6 to 1.6 days) without compromising disease resolution and patient safety. Of note, we were not able to assess the e&ect of PCT on mortality due to the very low risk situation with only one non-survivor (control group) among the 1008 included participants. The available evidence from RCTs, as summarised in this report, supports the use of PCT for de-escalation of antibiotic therapy for people with ARIs. The same may not be true for escalation of antibiotic therapy when PCT levels increase as demonstrated in a recent large sepsis trial (Jensen 2011), where PCT-guided escalation of diagnostic procedures and antimicrobial therapy in the ICU did not improve survival and led to organ-related harm and prolonged ICU stays. A U T H O R S '   C O N C L U S I O N S Implications for practice Emerging bacterial resistance to multiple antibiotic agents calls for more stringent e&orts to reduce the empiric use of antimicrobial agents in self limited and non-bacterial diseases and to shorten the duration of antibiotic treatment in bacterial infection with clinical resolution. The results of our study suggest that procalcitonin (PCT) is a safe and e&ective tool to guide clinical decisions for antibiotic initiation and duration of treatment. In all trials, PCT was used to inform physicians about the need for initiation or discontinuation of antibiotic therapy, or both. However, there were di&erences in PCT protocols among trials depending on the clinical setting (see Table 1 for details about PCT recommendations used in the individual trials) (Schuetz 2011a; Schuetz 2015). In brief, PCT was mainly used to inform about initiation of antibiotic treatment in primary care trials, and re-measurement of PCT was recommended in participants not being treated with antibiotics and not showing a resolution of illness  at follow-up. In the emergency room and hospital ward setting, PCT was used to inform about initiation of antibiotic treatment (mainly in low-risk patients with bronchitis or chronic obstructive pulmonary disease exacerbation), and also about discontinuation of treatment in community-acquired pneumonia patients. In intensive care unit patients, PCT was mainly used to monitor treatment and discontinue antibiotics in participants with clinical improvement and a drop in PCT levels. Thus for clinical practice, PCT should also be adapted to clinical settings and the risk of patients - similar to patients with suspicion of pulmonary embolism where D-dimer levels are used di&erently depending on the pre-test probability (Konstantinides 2008). The use of PCT to guide initiation and duration of antibiotic treatment in people with acute respiratory infections (ARIs) was associated with lower mortality rates and significantly reduced antibiotic consumption and associated side e&ects across di&erent clinical settings and ARI diagnoses. Of note, mortality was very low in primary care patients, and we were thus not able to assess the e&ect of PCT on mortality. The use of PCT embedded in clinical algorithms has the potential to improve the antibiotic management of ARI patients and has substantial clinical and public health implications to reduce antibiotic exposure and the associated risk of antibiotic resistance. Several assays for the measurement of PCT are currently available (Schuetz 2017), and the US Food and Drug Administration recently cleared the Vidas assay, among others, for antibiotic stewardship and prognostication of patients using a PCT kinetics algorithm (Schuetz 2016). Importantly, all trials have used highly sensitive assays to measure PCT in order to have optimal sensitivity and thus test performance. Factors such as accessibility and time taken to get reports of the tests are equally important in whether PCT will be used in the clinical decision-making process for antibiotic therapy in ARIs. In this regard, a point-of-care test would be important, especially for the primary care setting (Kutz 2016). Importantly, all trials included PCT into clinical algorithms, and physicians could deviate from the PCT algorithm if needed. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 17 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Poststudy surveys have been published in order to better understand the e&ects and challenges of PCT testing in clinical practice (Albrich 2012; Balk 2017). Implications for research Future studies should establish cost-e&ectiveness by considering country-specific costs of PCT measurement (around USD 20 to USD 30 per sample) and potential savings in consumption of antibiotics and other healthcare resources (Stojanovic 2017). In addition, it would be interesting to conduct a head-to-head trial comparing a PCT strategy to a strategy based on another biomarker, such as C-reactive protein (CRP) or interleukin-6 (Meili 2015; Meili 2016). A similar randomised controlled trial was recently conducted in primary care in the Netherlands with a treatment algorithm based on either CRP levels, communication training, or both, compared to a control group (Cals 2009). The trial authors reported a 42% relative reduction in antibiotic use with CRP guidance, which was similar to the e&ect of communication training in this setting. However, the usefulness of CRP for antibiotic guidance outside the primary care setting is not yet supported by controlled intervention trials. While there is strong evidence for the use of PCT in respiratory infections, its role in other infections remains unclear. Several studies have investigated PCT as a diagnostic and antibiotic stewardship marker in di&erent types of infections (Albrich 2012; Drozdov 2015; Sager 2017). However, larger trials powered for safety are needed to understand the e&ect of PCT outside respiratory infections. A C K N O W L E D G E M E N T S We thank all participating patients and sta& of the clinics of emergency medicine, internal medicine, and departments of clinical chemistry from all participating hospitals for their most helpful support during the individual studies. We also wish to thank the following people for commenting on the dra[ protocol: Hayley Edmonds, Anette Holm, Renato Seligman, Richard Shoemaker, and Roger Damoiseaux; and for reviewing the dra[ review we wish to thank Anne Lyddiatt, Noorin Bhimani, Anette Holm, Renato Seligman, Mark Jones, and Roger Damoiseaux. We also thank Qing Wang (for translating Chinese articles) and Benjamin Kasenda (for helping with quality assessment of trials in which the primary investigators were involved). Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews R E F E R E N C E S   References to studies included in this review Annane 2013 {published data only} Annane D, Maxime V, Faller JP, Mezher C, Clec'h C, Martel P, et al. Procalcitonin levels to guide antibiotic therapy in adults with non-microbiologically proven apparent severe sepsis: a randomised controlled trial. BMJ Open 2013;3(2):pii: e002186. Bloos 2016 {published data only} Bloos F, Trips E, Nierhaus A, Briegel J, Heyland DK, Jaschinski U, et al. E&ect of sodium selenite administration and procalcitonin-guided therapy on mortality in patients with severe sepsis or septic shock: a randomized clinical trial. JAMA Internal Medicine 2016;176(9):1266-76. Bouadma 2010 {published data only} Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010;375(9713):463-74. Branche 2015 {published data only} Branche AR, Walsh EE, Vargas R, Hulbert B, Formica MA, Baran A, et al. Serum procalcitonin measurement and viral testing to guide antibiotic use for respiratory infections in hospitalized adults: a randomized controlled trial. Journal of Infectious Diseases 2015;212(11):1692-700. Briel 2008 {published data only} Briel M, Schuetz P, Mueller B, Young J, Schild U, Nusbaumer C, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Archives of Internal Medicine 2008;168(18):2000-7. Burkhardt 2010 {published data only} Burkhardt O, Ewig S, Haagen U, Giersdorf S, Hartmann O, Wegscheider K, et al. Procalcitonin guidance and reduction of antibiotic use in acute respiratory tract infection. European Respiratory Journal 2010;36(3):601-7. Christ-Crain 2004 {published data only} Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay M, Huber P, Tamm M, et al. E&ect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004;1363(9409):600-7. Christ-Crain 2006 {published data only} Christ-Crain M, Stolz D, Bingisser R, Muller C, Miedinger D, Huber PR, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. American Journal of Respiratory and Critical Care Medicine 2006;174(1):84-93. Corti 2016 {published data only} Corti C, Fally M, Fabricius-Bjerre A, Mortensen K, Jensen BN, Andreassen HF, et al. Point-of-care procalcitonin test to reduce antibiotic exposure in patients hospitalized with acute exacerbation of COPD. International Journal of Chronic Obstructructive Pulmonary Disease 2016;11:1381-9. [DOI: 10.2147/COPD.S104051] De Jong 2016 {published data only} De Jong E, van Oers JA, Beishuizen A, Vos P, Vermeijden WJ, Haas LE, et al. E&icacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infectious Diseases 2016;16(7):819-27. Deliberato 2013 {published data only} Deliberato RO, Marra AR, Sanches PR, Martino MD, Ferreira CE, Pasternak J, et al. Clinical and economic impact of procalcitonin to shorten antimicrobial therapy in septic patients with proven bacterial infection in an intensive care setting. Diagnostic Microbiology and Infectious Disease 2013;76(3):266-71. Ding 2013 {published data only} Ding J, Chen Z, Feng K. Procalcitonin-guided antibiotic use in acute exacerbations of idiopathic pulmonary fibrosis. International Journal of Medical Sciences 2013;10(7):903-7. Hochreiter 2009 {published data only} Hochreiter M, Kohler T, Schweiger AM, Keck FS, Bein B, von Spiegel T, et al. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Critical Care 2009;13(3):R83. Kristo>ersen 2009 {published data only} Kristo&ersen KB, Sogaard OS, Wejse C, Black FT, Greve T, Tarp B, et al. Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission - a randomized trial. Clinical Microbiology and Infection 2009;15(5):481-7. Layios 2012 {published data only} Layios N, Lambermont B, Canivet JL, Morimont P, Preiser JC, Garweg C, et al. Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients. Critical Care Medicine 2012;40(8):2304-9. Lima 2016 {published data only} Lima SS, Nobre V, de Castro Romanelli RM, Clemente WT, da Silva Bittencourt HN, Melo AC, et al. Procalcitonin- guided protocol is not useful to manage antibiotic therapy in febrile neutropenia: a randomized controlled trial. Annals of Hematology 2016;95(7):1169-76. Long 2009 {published data only} Long W, Deng XQ, Tang JG, Xie J, Zhang YC, Zhang Y, et al. Procalcitonin guidance for reduction of antibiotic use in low-risk outpatients with community acquired pneumonia. Zhonghua Nei Ke Za Zhi 2009;48(3):216-9. Long 2011 {published data only} Long W, Deng X, Zhang Y, Lu G, Xie J, Tang J. Procalcitonin guidance for reduction of antibiotic use in low-risk outpatients with community acquired pneumonia. Respirology 2011;76(1):266-9. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 19 https://doi.org/10.2147%2FCOPD.S104051 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Long 2014 {published data only} Long W, Li LJ, Huang GZ, Zhang XM, Zhang YC, Tang JG, et al. Procalcitonin guidance for reduction of antibiotic use in patients hospitalized with severe acute exacerbations of asthma: a randomized controlled study with 12-month follow- up. Critical Care 2014;18(5):471. Maravić-Stojković 2011 {published data only} Maravić-Stojković V, Laušević-Vuk L, Jović M, Ranković A, Borzanović M, Marinković J. Procalcitonin-based therapeutic strategy to reduce antibiotic use in patients a[er cardiac surgery: a randomized controlled trial. Srpski Arhiv Celokupno Lekarstvo 2011;139(11-12):736-42. Najafi 2015 {published data only} Najafi A, Khodadadian A, Sanatkar M, Shariat Moharari R, Etezadi F, Ahmadi A, et al. The comparison of procalcitonin guidance administer antibiotics with empiric antibiotic therapy in critically ill patients admitted in intensive care unit. Acta Medica Iranica 2015;53(9):562-7. Nobre 2008 {published data only} Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. American Journal of Respiratory and Critical Care Medicine 2009;177(5):498-505. Ogasawara 2014 {published data only} Ogasawara T, Umezawa H, Naito Y, Takeuchi T, Kato S, Yano T, et al. Procalcitonin-guided antibiotic therapy in aspiration pneumonia and an assessment of the continuation of oral intake. Respiratory Investigation 2014;52(2):107-13. Oliveira 2013 {published data only} Oliveira CF, Botoni FA, Oliveira CR, Silva CB, Pereira HA, Serufo JC, et al. Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial. Critical Care Medicine 2013;41(10):2336-43. Schroeder 2009 {published data only} Schroeder S, Hochreiter M, Koehler T, Schweiger AM, Bein B, Keck FS, et al. Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study. Langenbecks Archives of Surgery 2009;394(2):221-6. Schuetz 2009 {published data only} Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. E&ect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059-66. Shehabi 2014 {published data only} Shehabi Y, Sterba M, Garrett PM, Rachakonda KS, Stephens D, Harrigan P, et al. ProGUARD Study Investigators, ANZICS Clinical Trials Group. Procalcitonin algorithm in critically ill adults with undi&erentiated infection or suspected sepsis. A randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2014;190(10):1102-10. Stolz 2007 {published data only} Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131(1):9-19. Stolz 2009 {published data only} Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. European Respiratory Journal 2009;34(6):1364-75. Tang 2013 {published data only} Tang J, Long W, Yan L, Zhang Y, Xie J, Lu G, et al. Procalcitonin guided antibiotic therapy of acute exacerbations of asthma: a randomized controlled trial. BMC Infectious Diseases 2013;13:596. [DOI: 10.1186/1471-2334-13-596] Verduri 2015 {published data only} Verduri A, Luppi F, D'Amico R, Balduzzi S, Vicini R, Liverani A, et al. Antibiotic treatment of severe exacerbations of chronic obstructive pulmonary disease with procalcitonin: a randomized noninferiority trial. PLoS ONE 2015;10(3):e0118241. Wang 2016 {published data only} Wang JX, Zhang SM, Li XH, Zhang Y, Xu ZY, Cao B. Acute exacerbations of chronic obstructive pulmonary disease with low serum procalcitonin values do not benefit from antibiotic treatment: a prospective randomized controlled trial. International Journal of Infectious Diseases 2016;48:40-5. [DOI: 10.1016/j.ijid.2016.04.024]   References to studies excluded from this review Dharaniyadewi 2013 {published data only} Dharaniyadewi D, Lie KC, Sukmana N, Rumende CM. E&ect of semi-quantitative procalcitonin assay on the adequacy of empirical antibiotics and mortality in septic patients. Citical Care 2013;17(Suppl 4):P15. Esposito 2012 {published data only} Esposito S,  Tagliabue C,  Picciolli I,  Semino M,  Sabatini C,  Consolo S,  et al. Procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia. Respiratory Medicine 2011;105(12):1939-45. Heyland 2011 {published data only} Heyland DK, Johnson AP, Reynolds SC, Muscedere J. Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic review and an economic evaluation. Critical Care Medicine 2011;39(7):1792-9. Jensen 2011 {published data only} Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen MH, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Critical Care Medicine 2011;39(9):2048-58. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20 https://doi.org/10.1186%2F1471-2334-13-596 https://doi.org/10.1016%2Fj.ijid.2016.04.024 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews Jones 2007 {published data only} Jones AE, Fiechtl JF, Brown MD, Ballew JJ, Kline JA. Procalcitonin test in the diagnosis of bacteremia: a meta- analysis. Annals of Emergency Medicine 2007;50(1):34-41. Kook 2012 {published data only} Kook JL,  Chao SR,  Le J,  Robinson PA. Impact of the use of procalcitonin assay in hospitalised patients with pneumonia at a community care hospital. Infection Control and Hospital Epidemiology 2012;33(4):424-6. Liew 2011 {published data only} Liew YX,  Chlebicki MP,  Lee W,  Hsu LY,  Kwa AL. Use of procalcitonin (PCT) to guide discontinuation of antibiotic use in an unspecified sepsis is an antimicrobial stewardship program (ASP). European Journal of Clinical Microbiology and Infectious Diseases 2011;30:853-5. Liu 2013 {published data only} Liu BH, Li HF, Lei Y, Zhao SX, Sun ML. Clinical significance of dynamic monitoring of procalcitonin in guiding the use of antibiotics in patients with sepsis in ICU. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2013;25(11):690-3. Qu 2012 {published data only} Qu R,  Ji Y,  Ling Y,  Ye CY,  Yang SM,  Liu YY,  et al. Procalcitonin is a good tool to guide duration of antibiotic therapy in patients with severe acute pancreatitis. A randomized prospective single-center controlled trial. Saudi Medical Journal 2012;33(4):382-7. Saeed 2011 {published data only} Saeed K, Dryden M, Bourne S, Paget C, Proud A. Reduction in antibiotic use through procalcitonin testing in patients in the medical admission unit or intensive care unit with suspicion of infection. Journal of Hospital Infection 2011;78(4):289-92. Schuetz 2010 {published data only} Schuetz P, Batschwaro& M, Dusemund F, Albrich W, Burgi U, Maurer M, et al. E&ectiveness of a procalcitonin algorithm to guide antibiotic therapy in respiratory tract infections outside of study conditions: a post-study survey. European Journal of Clinical Microbiology and Infectious Diseases 2010;29(3):269-77. Simmonds 2005 {published data only} Simmonds MC, Higgins JP, Stewart LA, Tierney JF, Clarke MJ, Thompson SG. Meta-analysis of individual patient data from randomized trials: a review of methods used in practice. Clinical Trials 2005;2(3):209-17. Simon 2004 {published data only} Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clinical Infectious Diseases 2004;39(2):206-17. Stocker 2010 {published data only} Stocker M, Fontana M, el Helou S, Wegscheider K, Berger TM. Use of procalcitonin-guided decision-making to shorten antibiotic therapy in suspected neonatal early-onset sepsis: prospective randomized intervention trial. Neonatology 2010;97(2):165-74. Tang 2007 {published data only} Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infectious Diseases 2007;7(3):210-7. Tang 2009 {published data only} Tang H, Huang T, Jing J, Shen H, Cui W. E&ect of procalcitonin- guided treatment in patients with infections: a systematic review and meta-analysis. Infection 2009;37(6):497-507. Uzzan 2006 {published data only} Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and a[er surgery or trauma: a systematic review and meta- analysis. Critical Care Medicine 2006;34(7):1996-2003.   References to ongoing studies NCT02130986 {unpublished data only} *  NCT02130986. Procalcitonin Antibiotic Consensus Trial (ProACT). clinicaltrials.gov/ct2/show/study/NCT02130986 First received: May 1, 2014. NCT02261610 {unpublished data only} *  NCT02261610. Pulmonary Embolism and PCT. PE-PCT Study. clinicaltrials.gov/ct2/show/NCT02261610 First received: September 5, 2014. NCT02332577 {unpublished data only} *  NCT02332577. Study to compare the e&icacy of pristinamycin (Pyostacine) versus amoxicillin in the treatment of acute community acquired pneumonia. clinicaltrials.gov/ct2/show/ NCT02332577 First received: January 5, 2015. NCT02440828 {unpublished data only} *  NCT02440828. Addition of tobramycin inhalation in the treatment of ventilator associated pneumonia (VAPORISE). clinicaltrials.gov/ct2/show/NCT02440828 First received: March 13, 2015. NCT02787603 {unpublished data only} *  NCT02787603. Procalcitonin in Early Antibiotic Interruption in Patient With Bacterial Pulmonary infeCtion and Acute Heart Failure (EPICAD). clinicaltrials.gov/ct2/show/NCT02787603 First received: May 25, 2016. NCT02862314 {unpublished data only} *  NCT02862314. PROcalcitonin Pneumonia/Pneumonitis Associated With ASPIration (PROPASPI). clinicaltrials.gov/ct2/ show/NCT02862314 First received: July 29, 2016. NCT02931409 {unpublished data only} *  NCT02931409. Intraoperative PEEP optimization: e&ects on postoperative pulmonary complications and inflammatory response. clinicaltrials.gov/ct2/show/NCT02931409 First received: October 5, 2016. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 Cochrane Library Trusted evidence. Informed decisions. Better health.     Cochrane Database of Systematic Reviews   Additional references Albrich 2012 Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R, Kuhn F, et al. E&ectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in "real life": an international, multicenter post-study survey (ProREAL). Archives of Internal Medicine 2012;172(9):715-22. Arnold 2005 Arnold SR, Straus SE. Interventions to improve antibiotic prescribing practices in ambulatory care. Cochrane Database of Systematic Reviews 2005, Issue 4. [DOI: 10.1002/14651858.CD003539.pub2] Atkins 2004 Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, et al. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490. Balk 2017 Balk RA, Kadri SS, Cao Z, Robinson SB, Lipkin C, Bozzette SA. E&ect of procalcitonin testing on health-care utilization and costs in critically ill patients in the United States. Chest 2017;151(1):23-33. Cals 2009 Cals JW, Butler CC, Hopstaken RM, Hood K, Dinant GJ. E&ect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial. BMJ 2009;338:b1374. Doan 2014 Doan Q, Enarson P, Kissoon N, Klassen TP, Johnson DW. Rapid viral diagnosis for acute febrile respiratory illness in children in the Emergency Department. Cochrane Database of Systematic Reviews 2014, Issue 9. [DOI: 10.1002/14651858.CD006452.pub4] Drozdov 2015 Drozdov D, Schwarz S, Kutz A, Grolimund E, Rast AC, Steiner D, et al. Procalcitonin and pyuria-based algorithm reduces antibiotic use in urinary tract infections: a randomized controlled trial. BMC Medicine 2015;13(1):104. Evans 2002 Evans AT, Husain S, Durairaj L, Sadowski LS, Charles-Damte M, Wang Y. Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial. Lancet 2002;359(9318):1648-54. Gonzales 1997 Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997;278(11):901-4. Goossens 2005 Goossens H, Ferech M, Vander Stichele R, Elseviers M. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005;365(9435):579-87. GRADEpro GDT 2014 [Computer program] GRADE Working Group, McMaster University. GRADEpro GDT. Version (accessed April 2017). Hamilton (ON): GRADE Working Group, McMaster University, 2014. Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60. Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collab