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Three Part Question

[In adults presenting to the emergency department with acute exacerbation of chronic obstructive pulmonary disease (COPD)] can [use of a procalcitonin algorithm compared to physician gestalt] result in [lower rates of antibiotic consumption with no adverse effects]

Clinical Scenario

A 78 year old female presents to your emergency department reporting increased wheezing over the last 24 hours. She reports a mildly productive cough and denies fever. A chest x-ray reveals no clear evidence of pneumonia. In addition to therapy for what you believe is a COPD exacerbation, you consider the possibility of bacterial infection. A colleague mentions that they are using procalcitonin as a biomarker to guide antibiotic therapy for patients with potential respiratory infection on the intensive care unit. You wonder if there is any evidence assessing the utility of procalcitonin for this indication in the emergency department.

Search Strategy

Medline 1946-12/14 using OVID interface, Cochrane Library (2014),
PubMed clinical queries.[(Exp COPD) OR (exp lower respiratory tract infections) AND (exp procalcitonin)]. Limit to Randomized Controlled Trial and English language

Ovid MEDLINE(R) <1946 to February Week 4 2015
(COPD.mp. or exp Pulmonary Disease, Chronic Obstructive/) AND (procalcitonin.mp.) Limit to English language and humans, Published 2011–Current

The Cochrane Library Issue 2 of 12, February 2015
(MeSH descriptor: [Pulmonary Disease, Chronic Obstructive] explode all trees OR COPD ti,ab,kw (Word variations have been searched)) AND (procalcitonin:ti,ab,kw (Word variations have been searched) There are 15 results, one of which is a recently conducted systematic review

Search Outcome

Sixteen results of which five were directly relevant to the three-part question. Four of these papers were included in the systematic review and have therefore been superseded. However, COPD subgroup analyses were conducted in several of the individual papers and are therefore reported in the table below, within the systematic review. A further prospective observational cohort study was identified subsequent to the systematic review; this is reported separately below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Scheutz et al 2012 USA	Patients with acute respiratory infection (ARI) recruited to randomised controlled trials comparing a procalcitonin-guided algorithm vs control, for initiation and duration of antibiotic therapy. The review incorporated patients with upper or lower ARI from a variety of clinical settings (primary care, emergency department, intensive care) and with a variety of underlying pathology (asthma, COPD, HAP, CAP, VAP)	Systematic review and meta-analysis of RCT data including 4111 patients.	Odds ratio for mortality at 30 days (subgroup by setting for emergency medicine)	1.05 (95% CI 0.75 to 1.52)	No specific subgroup analysis for COPD within Cochrane review therefore results may be skewed by inclusion of patients with URTI. Included trials non-inferiority therefore not overtly powered to detect small mortality differences—risk of type 2 error. Not overtly clear how much weight is given to using procalcitonin to initiate vs early stopping of antibiotics
			Odds ratio for treatment failure at 30 days (subgroup by setting for emergency medicine)	0.78 (95% CI 0.62 to 0.96)
			Median adjusted difference in days of antibiotic exposure across all clinical settings	-3.47 (95% CI -3.78 to -3.17)
			Subgroup analysis of Scheutz et al (2009)	Antibiotic prescription rate reduced by 44% with no significant difference in clinical outcomes detected
			Subgroup analysis of Kristoffersen et al (2009)	Antibiotic prescription rate reduced by 40% with no significant difference in clinical outcomes detected
			Subgroup analysis of Stolz et al	Antibiotic prescription rate reduced by 21% with no significant difference in clinical outcomes detected
			Subgroup analysis of Christ-Crain et al (2004)	Antibiotic prescription rate reduced by 49% with no significant difference in clinical outcomes detected
Bafadhel et al 2011 UK	319 adult patients with a combination of clinically diagnosed pneumonia (62), acute asthma (96) or exacerbation of COAD (161).	Prospective observational cohort.	AUC for procalcitonin guided diagnosis of pneumonic process	0.93 (95% CI 0.88 to 0.98)	Gold standard appears clinician led - therefore subjective influence and incorporation bias possible, although procalcitonin results were reported to be blinded. No direct comparison of how PCT would reduce antibiotic consumption. No clear follow up data regarding complication rates, mortality or treatment failure and how PCT could have impacted on this.

Comment(s)

Procalcitonin is a biomarker released in direct response to bacterial infection within multiple tissues. Conversely, production is inhibited by interferon gamma, a cytokine release during viral infection. It follows that there may be a role in differentiating bacterial from simple acute COPD exacerbations. There is already convincing data to suggest a high degree of correlation between increasing levels of procalcitonin and the presence of bacterial infection. What is less clear is whether using procalcitonin at predefined cut-offs in the emergency department is a safe and effective strategy to guide antibiotic prescription. The data reviewed here suggest that procalcitonin may be used to guide therapy without an increased rate of death or other adverse outcomes such as prolonged hospital stay, intensive care unit admission or re-exacerbation. This could serve to promote antimicrobial stewardship, decrease antibiotic prescription rates among patients with nonbacterial COPD infections, decrease rates of adverse reactions to antibiotics and potentially decrease cost through reductions in hospital admissions/LOS and reduced consumption.

Editor Comment

AUC, area under the curve; CAP, community acquired pneumonia; COAD, chronic obstructive airways disease; COPD, chronic obstructive pulmonary disease; HAP, hospital acquired pneumonia; LOS, length of stay; PCT, procalcitonin; RCT, randomised controlled trial; URTI, upper respiratory tract infection; VAP, ventilator associated pneumonia.

Clinical Bottom Line

There is increasing evidence that procalcitonin may be a useful adjunct in guiding initiation and duration of antibiotic therapy in the setting of chronic obstructive pulmonary disease exacerbation. Further validation studies are required to confirm the safety and benefits of withholding antibiotics based on a procalcitonin algorithm. No cost effectiveness data are available as yet.

Level of Evidence

Level 1 - Recent well-done systematic review was considered or a study of high quality is available.

References

1. Schuetz P, Müller B, Christ-Crain M et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review) The Cochrane Collaboration 2012, Issue 9. Art. No.: CD007498. DOI: 10.1002/14651858.CD007498.pub2.
2. Bafadhel M, Clark TW, Reid C, et al. Procalcitonin and C-Reactive Protein in Hospitalized Adult Patients With Community-Acquired Pneumonia or Exacerbation of Asthma or COPD Chest 2011;139:1410-1418.
3. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302:1059–66.
4. Kristoffersen KB, Sogaard OS, Wejse C, et al. Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission – a randomized trial. Clin Microbiol Infect 2009;15: 481–7.
5. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007;131:9–19.
6. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2002;363:600–7.