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Study flow diagram.Abbreviations: ARI: acute respiratory infection; IPD: individual participant data; RCT: randomised controlled trial
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Figure 1

Study flow diagram.

Abbreviations: ARI: acute respiratory infection; IPD: individual participant data; RCT: randomised controlled trial

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
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Figure 3

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Funnel plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.
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Figure 4

Funnel plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.

Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.
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Figure 5

Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.1 Mortality at 30 days.

Forest plot of comparison: 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, outcome: 1.2 Treatment failure at 30 days.
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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.

Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 1 Mortality at 30 days.
Figuras y tablas -
Analysis 1.1

Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 1 Mortality at 30 days.

Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 2 Treatment failure at 30 days.
Figuras y tablas -
Analysis 1.2

Comparison 1 Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting, Outcome 2 Treatment failure at 30 days.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 1 Mortality at 30 days stratified by adherence.
Figuras y tablas -
Analysis 2.1

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 1 Mortality at 30 days stratified by adherence.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 2 Treatment failure at 30 days stratified by adherence.
Figuras y tablas -
Analysis 2.2

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 2 Treatment failure at 30 days stratified by adherence.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 3 Mortality at 30 days stratified by allocation concealment.
Figuras y tablas -
Analysis 2.3

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 3 Mortality at 30 days stratified by allocation concealment.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 4 Treatment failure at 30 days stratified by allocation concealment.
Figuras y tablas -
Analysis 2.4

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 4 Treatment failure at 30 days stratified by allocation concealment.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 5 Mortality at 30 days stratified by blinded outcome assessment.
Figuras y tablas -
Analysis 2.5

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 5 Mortality at 30 days stratified by blinded outcome assessment.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 6 Treatment failure at 30 days stratified by blinded outcome assessment.
Figuras y tablas -
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.

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 7 Mortality at 30 days stratified by follow up.
Figuras y tablas -
Analysis 2.7

Comparison 2 Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses, Outcome 7 Mortality at 30 days stratified by follow up.

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Standard care

PCTalgorithm

Mortality
Follow‐up: 30 days

Study population

OR 0.83
(0.70 to 0.99)

6708
(26 studies)

⊕⊕⊕⊕
High1

100 per 1000

86 per 1000

(76 to 95)

Treatment failure
Clinical assessment3
Follow‐up: 30 days

Study population

OR 0.90
(0.80 to 1.01)

6708
(26 studies)

⊕⊕⊕⊝
Moderate2 3

249 per 1000

230 per 1000

(216 to 245)

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 exposure 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.
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 differing 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 after 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 effects from antibiotics, and none of these trials were conducted in the ICU setting.

Figuras y tablas -
Summary of findings for the main comparison. Procalcitonin algorithm compared to standard care for guiding antibiotic therapy in acute respiratory tract infections
Table 1. Characteristics of included trials

Study ID

Country

Setting, type of trial

Clinical diagnosis

Type of PCTalgorithm and PCTcut‐offs used (µg/L)

N: ARI participants (study total)

Primary endpoint

Follow‐up time

Reasons for exclusion of patients

Annane 2013

France

ICU, multicentre

Severe sepsis without overt source of infection and negative blood culture

Initiation and duration; R against AB: < 0.5 (< 0.25); R for AB: > 0.5 (> 5.0)

0 (62)

Participants on AB on day 5 post randomisation

Hospital stay

62 non‐ARI patients (4 of them with post randomisation consent withdrawal)

Bloos 2016

Germany

ICU, multicentre

Severe sepsis or septic shock

Discontinuation at day 4, 7, and 10; R against AB: < 1.0 or > 50% drop to previous value

219 (1180)

28‐day mortality

3 months

91 post randomisation exclusions (informed consent not obtainable), 870 not ARI patients

Bouadma 2010

France

ICU, multicentre

Suspected bacterial infections during ICU stay without prior AB (> 24 h)

Initiation and duration; R against AB: < 0.5 (< 0.25); R for AB: > 0.5 (> 1.0)

394 (630)

All‐cause mortality

2 months

9 post randomisation exclusions (8 withdrew consent, 1 randomised twice); 227 non‐ARI patients

Branche 2015

USA

ED, medical ward, single centre

Lower ARI

Initiation and duration; R against AB: < 0.25 (< 0.1); R for AB: > 0.25 (> 0.5)

265 (300)

Antibiotic exposure and safety

3 months

35 non‐ARI patients

Briel 2008

Switzerland

Primary care, multicentre

Upper and lower ARI

Initiation and duration; R against AB: < 0.25 (< 0.1); R for AB: > 0.25 (> 0.5)

458 (458)

Days with restricted activities

1 month

No exclusions

Burkhardt 2010

Germany

Primary care, multicentre

Upper and lower ARI

Initiation; R against AB: < 0.25; R for AB: > 0.25

550 (571)

Days with restricted activities

1 month

21 post randomisation exclusions (2 withdrew consent, 1 due to loss of sample, 15 with autoimmune, inflammatory, or systemic disease, 2 with advanced liver disease, 1 with prior use of antibiotics)

Christ‐Crain 2004

Switzerland

ED, single centre

Lower ARI with X‐ray confirmation

Initiation; R against AB: < 0.25 (< 0.1); R for AB: > 0.25 (> 0.5)

219 (243)

AB use

2 weeks

24 non‐ARI patients

Christ‐Crain 2006

Switzerland

ED, medical ward, single centre

CAP with X‐ray confirmation

Initiation and duration; R against AB: < 0.25 (< 0.1); R for AB: > 0.25 (> 0.5)

286 (302)

AB use

6 weeks

16 non‐ARI patients

Corti 2016

Denmark

ED, single centre

AECOPD

Initiation and duration; R against AB < 0.25 (0.15)/80% decrease; R for AB > 0.25

120 (120)

AB use

28 days

No exclusions

De Jong 2016

Netherlands

ICU, multicentre

Critically ill patients with presumed infection

Duration; R against AB: < 0.5 or > 80% drop

994 (1575)

AB use

1 year

29 post randomisation exclusions (25 protocol violations, 4 withdrew informed consent), 552 non‐ARI patients

Deliberato 2013

Brazil

ICU, single centre

Septic patients with proven bacterial infection

Duration; R against AB: < 0.5 or > 90% drop

66 (81)

AB use

ICU discharge or 14 days' post randomisation

15 non‐ARI patients

Ding 2013

China

ICU, single centre

Acute exacerbation of pulmonary fibrosis

Initiation and duration; R against AB: < 0.25; R for AB: > 0.25

0 (78)

AB use

1 month

10 post randomisation exclusions (7 lost to follow‐up, 3 withdrew informed consent), 68 data not shared

Hochreiter 2009

Germany

Surgical ICU, single centre

Suspected bacterial infections and > 1 SIRS criteria

Duration; R against AB: < 1 or > 65% drop over 3 d

43 (110)

AB use

Hospital stay

67 non‐ARI patients

Kristoffersen 2009

Denmark

ED, medical ward, multicentre

Lower ARI without X‐ray confirmation

Initiation and duration; R against AB: < 0.25; R for AB: > 0.25 (> 0.5)

210 (223)

AB use

Hospital stay

13 post randomisation exclusions (3 no PCT testing, 6 not meeting inclusion criteria, 4 withdrew informed consent)

Layios 2012

Belgium

ICU, single centre

Suspected infection

Initiation; R against AB: < 0.5 (< 0.25); R for AB: > 0.5 (> 1.0)

160 (509)

AB use

1 month

120 no PCT measurements, 10 missing data, 219 non‐ARI patients

Lima 2016

Brazil

ED, medical ward, single centre

Febrile neutropenia

Duration; R against AB: < 0.5 for 2 days or > 90% drop than highest measured concentration

0 (62)

AB use

28 days

1 post randomisation exclusion (withdrew informed consent), 62 non‐ARI patients

Long 2009

China

ED, outpatients, single centre

CAP with X‐ray confirmation

Initiation and duration; R against AB: < 0.25; R for AB: > 0.25

127 (149)

AB use

1 month

22 post randomisation exclusions due to withdrawal of consent

Long 2011

China

ED, outpatients, single centre

CAP with X‐ray confirmation

Initiation and duration; R against AB: < 0.25; R for AB: > 0.25

156 (172)

AB use

1 month

16 post randomisation exclusions (6 lost to follow‐up, 7 withdrew consent, 3 with final diagnosis other than CAP)

Long 2014

China

ED, single centre

Severe acute exacerbation of asthma

Initiation; R against AB: < 0.25 (< 0.1); R for AB: > 0.25

180 (180)

AB use

1 year

No exclusions

Maravić‐Stojković 2011

Serbia

ICU surgical, single centre

Infection after open heart surgery

Initiation; R for AB: > 0.5

5 (205)

AB use, AB cost

Hospital stay

200 non‐ARI patients

Najafi 2015

Iran

ICU, single centre

SIRS without apparent source of infection

Initiation; R for AB: > 2

0 (60)

AB use

Hospital stay

60 patient data not shared

Nobre 2008

Switzerland

ICU, single centre

Suspected severe sepsis or septic shock

Duration; R against AB: < 0.5 (< 0.25) or > 80% drop; R for AB: > 0.5 (> 1.0)

52 (79)

AB use

1 month

27 non‐ARI patients

Ogasawara 2014

Japan

Medical ward, single centre

Aspiration pneumonia

Predefined duration; AB for 3 d: < 0.5; AB for 5 d: 0.5 to 1.0; AB for 7 d: > 1

0 (105)

Relapse and 30‐day mortality

1 month

9 post randomisation exclusions (2 withdrew consent, 7 others), 96 data not shared

Oliveira 2013

Brazil

ICU, multicentre

Severe sepsis or septic shock

Discontinuation; initial < 1.0: R against AB: 0.1 at day 4; initial > 1.0: R against: > 90% drop

58 (97)

AB use

28 days or hospital discharge

3 post randomisation exclusions (2 withdrew consent, 1 technical problems), 36 patients with a final diagnosis other than ARI

Schroeder 2009

Germany

Surgical ICU, single centre

Severe sepsis following abdominal surgery

Duration; R against AB: < 1 or > 65% drop over 3 d

8 (27)

AB use

Hospital stay

19 non‐ARI patients

Schuetz 2009

Switzerland

ED, medical ward, multicentre

Lower ARI with X‐ray confirmation

Initiation and duration; R against AB: < 0.25 (< 0.1); R for AB: > 0.25 (> 0.5)

1304 (1381)

AB use

1 month

22 post randomisation exclusions due to withdrawal of consent, 55 non‐ARI patients

Shehabi 2014

Australia

ICU, multicentre

Suspected sepsis, undifferentiated infections

Duration; R against AB: < 0.25 (< 0.1) or > 90% drop

156 (400)

AB use

3 months

6 post randomisation exclusions (6 withdrew consent), 238 non‐ARI patients

Stolz 2007

Switzerland

ED, medical ward, single centre

Exacerbated COPD

Initiation and duration; R against AB: < 0.25 (< 0.1); R for AB: > 0.25 (> 0.5)

208 (226)

AB use

2 to 3 weeks

18 post randomisation exclusions (absence of COPD)

Stolz 2009

Switzerland, USA

ICU, multicentre

VAP when intubated > 48 h

Duration; R against AB: < 0.5 (< 0.25) or > 80% drop; R for AB: > 0.5 (> 1.0)

101 (101)

AB‐free days alive

1 month

No exclusions

Tang 2013

China

ED, single centre

Exacerbation of asthma

Initiation and duration; R against AB: < 0.25 (< 0.1); R for AB: > 0.25

0 (265)

AB use

6 weeks

10 post randomisation exclusions (5 lost to follow‐up, 3 died, 2 withdrew consent), 255 data not shared

Verduri 2015

Italy

ED, medical ward, multicentre

AECOPD

Initiation; R against AB:< 0.1; R for AB: > 0.25

178 (183)

Number of exacerbations

6 months

5 post randomisation exclusions (5 lost to follow‐up because they did not meet the inclusion criteria)

Wang 2016

China

ICU, single centre

AECOPD

All participants had initial PCT < 0.1; AB group treated with AB for at least 3 days, control group no AB in the first 10 days

191 (194)

Treatment success within 10 days

30 days

3 post randomisation exclusions (3 with pneumonia according to CT scan)

AB: antibiotic
AECOPD: acute exacerbation of chronic obstructive pulmonary disease
ARI: acute respiratory infection
CAP: community‐acquired pneumonia
COPD: chronic obstructive pulmonary disease
CT: computed tomography
d: days
ED: emergency department
h: hours
ICU: intensive care unit
PCT: procalcitonin
R: recommendation for or against antibiotics
SIRS: systemic inflammatory response syndrome
VAP: ventilator‐associated pneumonia

Figuras y tablas -
Table 1. Characteristics of included trials
Table 2. Baseline characteristics of included participants

Parameter

Control (n = 3372)

PCT group (n = 3336)

Demographics

Age (year), mean (SD)

61.2 ± 18.4

60.7 ± 18.8

Male gender, n (%)

1910 (56.6%)

1898 (56.9%)

Clinical setting, no (%)

Primary care

501 (14.9%)

507 (15.2%)

Emergency department

1638 (48.6%)

1615 (48.4%)

Intensive care unit

1233 (36.6%)

1214 (36.4%)

Primary diagnosis

Total upper ARI, n (%)

280 (8.3%)

292 (8.8%)

Common cold

156 (4.6%)

149 (4.5%)

Rhino‐sinusitis, otitis

67 (2.0%)

73 (2.2%)

Pharyngitis, tonsillitis

46 (1.4%)

61 (1.8%)

Total lower ARI, n (%)

3092 (91.7%)

3044 (91.2%)

Community‐acquired pneumonia

1468 (43.5%)

1442 (43.2%)

Hospital‐acquired pneumonia

262 (7.8%)

243 (7.3%)

Ventilator‐associated pneumonia

186 (5.5%)

194 (5.8%)

Acute bronchitis

287 (8.5%)

257 (7.7%)

Exacerbation of COPD

631 (18.7%)

621 (18.6%)

Exacerbation of asthma

127 (3.8%)

143 (4.3%)

Other lower ARI

131 (3.9%)

144 (4.3%)

Procalcitonin upon enrolment

PCT< 0.1 ug/L

921 (35.6%)

981 (30.9%)

PCT 0.1 to 0.25 ug/L

521 (20.1%)

608 (19.2%)

PCT > 0.25 to 0.5 ug/L

308 (11.9%)

383 (12.1%)

PCT > 0.5 to 2.0 ug/L

358 (13.8%)

520 (16.4%)

PCT > 2.0 ug/L

482 (18.6%)

679 (21.4%)

ARI: acute respiratory infection
COPD: chronic obstructive pulmonary disease
PCT: procalcitonin
SD: standard deviation

Figuras y tablas -
Table 2. Baseline characteristics of included participants
Table 3. Quality assessment of trials

Study ID

Allocation concealment

Blinded
outcome assessment

Follow‐up for mortality

Adherence to PCT algorithm in PCT group

Follow‐up for mortality

Annane 2013

Yes (central randomisation)

No

58/58 (100%)

63% adherence

LOS

Bloos 2016

Yes (central randomisation)

No

1045/1089 (96%)

49.6% adherence

28 days and 90 days

Bouadma 2010

Yes (central randomisation)

Yes

393/394 (100%)

47% adherence

28 days and 60 days

Branche 2015

Yes (central randomisation using blocks of 4)

No

250/300 (83.3%)

64% adherence

1 month and 3 months

Briel 2008

Yes (central randomisation)

Yes

454/458 (99%)

85% adherence

28 days

Burkhardt 2010

Yes (central randomisation)

Yes

546/550 (99%)

87% adherence

28 days

Christ‐Crain 2004

No (alternating weeks)

No

230/243 (95%)

83% adherence

10 to 14 days

Christ‐Crain 2006

Yes (sequentially numbered, opaque, sealed envelopes)

No

300/302 (99%)

87% adherence

56 days

Corti 2016

Yes (randomisation algorithm was concealed to treating clinicians and participants)

No

120/120 (100%)

61.1% adherence

28 days

De Jong 2016

Yes (central randomisation)

No

1546/1546 (100%)

44% adherence

28 days and 1 year

Deliberato 2013

Yes (opaque, sealed envelopes)

No

81/81 (100%)

52% adherence

LOS

Ding 2013

Yes (central randomisation)

No

68/78 (87.2%)

Not reported

30 days

Hochreiter 2009

No (unconcealed drawing of lots)

No

43/43 (100% until discharge)

Not reported

LOS

Kristoffersen 2009

Yes (central randomisation)

No

210/210 (100% until discharge)

59% adherence

LOS

Layios 2012

Not reported

No

509/509 (100%)

Not reported

Intensive care unit LOS

Lima 2016

Yes (sequentially numbered, opaque, sealed envelopes)

No

61/62 (98.4%)

73.3% adherence

28 days and 90 days

Long 2009

No (odd and even patient ID numbers)

No

127/127 (100%)

Not reported

Not reported

Long 2011

No (odd and even patient ID numbers)

No

156/156 (100%)

Not reported

28 days

Long 2014

Yes (central randomisation)

No

169/180 (93.9%)

96.6% adherence

LOS and 1 year

Maravić‐Stojković 2011

Yes (central randomisation)

No

205/205 (100%)

Not reported

30 days and LOS

Najafi 2015

Yes (central randomisation)

No

30/30 (100%)

Not reported

LOS

Nobre 2008

Yes (sequentially numbered, opaque, sealed envelopes)

No

52/52 (100%)

81% adherence

28 days and LOS

Ogasawara 2014

Not reported

No

96/96 (100%)

Not reported

30 days

Oliveira 2013

Yes (central randomisation)

No

94/94 (100%)

86.2% adherence

28 days

Schroeder 2009

No (unconcealed drawing of lots)

No

8/8 (100% until discharge)

Not reported

LOS

Schuetz 2009

Yes (central randomisation)

Yes

1358/1359 (100%)

91% adherence

28 days

Shehabi 2014

Yes (central randomisation)

Yes

394/394 (100%)

Not reported

LOS and 90 days

Stolz 2007

Yes (sequentially numbered, opaque, sealed envelopes)

Yes

208/208 (100%)

Not reported

6 months

Stolz 2009

Yes (sequentially numbered, opaque, sealed envelopes)

No

101/101 (100%)

Not reported

28 days

Tang 2013

Yes (sequentially numbered, opaque, sealed envelopes)

Yes

258/265 (97.4%)

Not reported

6 weeks

Verduri 2015

Yes (central randomisation)

No

178/178 (100%)

Not reported

6 months

Wang 2016

Yes (those responsible for allocation concealment were not involved in the measurement of results)

No

191/191 (100%)

82.3% adherence (17 participants in the control group received AB)

30 days

LOS: length of stay
PCT: procalcitonin

Figuras y tablas -
Table 3. Quality assessment of trials
Table 4. Clinical endpoints overall and stratified by setting and ARI diagnosis

Control group

PCT group

Measures of effect: adjusted OR or difference (95% CI), P value

P for interaction

Overall

3372

3336

30 days mortality, n (%)

336 (10.0%)

286 (8.6%)

0.83 (0.70 to 0.99), P = 0.037

NA

Treatment failure, n (%)

841 (24.9%)

768 (23.0%)

0.90 (0.80 to 1.01), P = 0.068

NA

Length of ICU stay, mean (±SD)

13.3 ± 16.0

13.7 ± 17.2

0.39 (‐0.81 to 1.58), P = 0.524

NA

Length of hospital stay, mean (±SD)

13.7 ± 20.6

13.4 ± 18.4

‐0.19 (‐0.96 to 0.58), P = 0.626

NA

Antibiotic‐related side effects, n (%)

336 (22.1%)

247 (16.3%)

0.68 (0.57 to 0.82), P < 0.001

NA

According to setting

Primary care

501

507

30 days mortality, n (%)

1 (0.2%)

0 (0.0%)

NA

NA

Treatment failure, n (%)

164 (32.7%)

159 (31.4%)

0.96 (0.73 to 1.25), P = 0.751

0.715

Days with restricted activities, mean (±SD)

8.9 ± 4.2

8.9 ± 4.1

0.07 (‐0.44 to 0.59), P = 0.777

NA

Antibiotic‐related side effects, n (%)

128 (25.7%)

102 (20.2%)

0.65 (0.46 to 0.91), P = 0.012

0.596

Emergency department

1638

1615

30 days mortality, n (%)

62 (3.8%)

57 (3.5%)

0.91 (0.63 to 1.33), P = 0.635

0.546

Treatment failure, n (%)

292 (17.8%)

259 (16.0%)

0.87 (0.72 to 1.05), P = 0.141

0.807

Length of hospital stay, mean (±SD)

8.2 ± 10.5

8.1 ± 7.5

‐0.14 (‐0.73 to 0.44), P = 0.631

0.684

Antibiotic‐related side effects, n (%)

208 (20.3%)

145 (14.4%)

0.66 (0.52 to 0.83), P = 0.001

0.596

Intensive care unit

1233

1214

30 days mortality, n (%)

273 (22.3%)

229 (19.0%)

0.84 (0.69 to 1.02), P = 0.081

0.619

Length of ICU stay, mean (±SD)

14.8 ± 16.2

15.3 ± 17.5

0.56 (‐0.82 to 1.93), P = 0.427

0.849

Length of hospital stay, mean (±SD)

26.3 ± 26.9

25.8 ± 23.9

‐0.33 (‐2.28 to 1.62), P = 0.739

0.641

According to diagnosis

Community‐acquired pneumonia

1468

1442

30 days mortality, n (%)

206 (14.1%)

175 (12.2%)

0.82 (0.66 to 1.03), P = 0.083

0.958

Treatment failure, n (%)

385 (26.2%)

317 (22.0%)

0.78 (0.66 to 0.93), P = 0.005

0.052

Length of ICU stay, mean (±SD)

10.5 ± 10.3

11.9 ± 13.3

1.45 (0.15 to 2.75), P = 0.029

0.119

Length of hospital stay, mean (±SD)

13.3 ± 15.7

13.9 ± 16.1

0.74 (‐0.25 to 1.73), P = 0.143

0.094

Antibiotic‐related side effects, n (%)

186 (27.7%)

127 (19.1%)

0.62 (0.48 to 0.80), P < 0.001

0.227

Exacerbation of COPD

631

621

30 days mortality, n (%)

24 (3.8%)

19 (3.1%)

0.8 (0.43 to 1.48), P = 0.472

0.847

Treatment failure, n (%)

110 (17.4%)

104 (16.7%)

0.94 (0.70 to 1.27), P = 0.704

0.676

Length of hospital stay, mean (±SD)

9.3 ± 13.9

8.4 ± 7.2

‐0.60 (‐1.84 to 0.64), P = 0.342

0.658

Antibiotic‐related side effects, n (%)

30 (10.9%)

29 (10.5%)

0.93 (0.53 to 1.63), P = 0.805

0.198

Acute bronchitis

287

257

30 days mortality, n (%)

0 (0.0%)

2 (0.8%)

NA

NA

Treatment failure, n (%)

55 (19.2%)

52 (20.2%)

1.11 (0.72 to 1.70), P = 0.643

0.4

Length of hospital stay, mean (±SD)

2.6 ± 5.7

2.2 ± 4.7

‐0.21 (‐0.90 to 0.48), P = 0.556

0.97

Antibiotic‐related side effects, n (%)

54 (21.6%)

39 (17.3%)

0.77 (0.49 to 1.22), P = 0.263

0.657

Ventilator‐associated pneumonia

186

194

30 days mortality, n (%)

29 (15.6%)

23 (12.0%)

0.75 (0.41 to 1.39), P = 0.366

0.644

Treatment failure, n (%)

51 (27.4%)

44 (22.7%)

0.78 (0.48 to 1.28), P = 0.332

0.522

Length of ICU stay, mean (±SD)

23.5 ± 20.5

21.8 ± 19.1

‐1.74 (‐5.64 to 2.17), P = 0.383

0.441

Length of hospital stay, mean (±SD)

33.8 ± 27.6

32.0 ± 23.1

‐2.14 (‐7.04 to 2.75), P = 0.391

0.448

Measures of effect: dichotomous outcomes are reported as adjusted OR (95% CI) and continuous outcomes are adjusted mean differences and confidence intervals

ARI: acute respiratory infection
CI: confidence interval
COPD: chronic obstructive pulmonary disease
ICU: intensive care unit
NA: not applicable
OR: odds ratio
PCT: procalcitonin
SD: standard deviation

Figuras y tablas -
Table 4. Clinical endpoints overall and stratified by setting and ARI diagnosis
Table 5. Sensitivity analysis

Mortality

Main analysis

Control group

PCT group

Adjusted OR (95% CI), P value

P for interaction

All participants

336 (10.0%)

286 (8.6%)

0.83 (0.70 to 0.99), P = 0.037

NA

Adherence

High adherence

82 (4.5%)

75 (4.1%)

0.88 (0.63 to 1.22), P = 0.434

0.617

Low adherence (< 70% or not reporting)

254 (16.4%)

211 (14.0%)

0.83 (0.67 to 1.02), P = 0.073

Allocation

Low risk for allocation concealment bias

305 (10.6%)

250 (8.8%)

0.80 (0.67 to 0.97), P = 0.021

0.229

High risk for allocation concealment bias (or not reporting)

31 (6.5%)

36 (7.3%)

1.12 (0.66 to 1.91), P = 0.672

Blinding

Blinded outcome assessment

113 (6.5%)

102 (5.9%)

0.85 (0.64 to 1.13), P = 0.259

0.537

No blinded outcome assessment

223 (13.8%)

184 (11.5%)

0.81 (0.65 to 1.01), P = 0.062

Follow‐up

Follow up for mortality at 1 month

275 (10.7%)

224 (8.9%)

0.81 (0.67 to 0.99), P = 0.039

0.325

Follow up for mortality < 1 month

61 (7.6%)

62 (7.6%)

0.94 (0.64 to 1.38), P = 0.756

Treatment failure

Control group

PCT group

Adjusted OR (95% CI), P value

P for interaction

All participants

841 (24.9%)

768 (23.0%)

0.90 (0.80 to 1.01), P = 0.068

NA

Adherence

High adherence

419 (23.1%)

381 (21.0%)

0.89 (0.76 to 1.04), P = 0.148

0.752

Low adherence (< 70% or not reporting)

422 (27.1%)

387 (25.5%)

0.92 (0.77 to 1.08), P = 0.301

Allocation

Low risk for allocation concealment bias

776 (26.8%)

699 (24.6%)

0.89 (0.79 to 1.01), P = 0.069

0.486

High risk for allocation concealment bias (or not reporting)

65 (13.6%)

69 (13.8%)

0.99 (0.68 to 1.44), P = 0.939

Blinding

Blinded outcome assessment

412 (23.5%)

367 (21.1%)

0.88 (0.75 to 1.03), P = 0.117

0.574

No blinded outcome assessment

429 (26.5%)

401 (25.1%)

0.94 (0.79 to 1.11), P = 0.438

CI: confidence interval
NA: not applicable
OR: odds ratio
PCT: procalcitonin

Figuras y tablas -
Table 5. Sensitivity analysis
Table 6. Antibiotic treatment overall and stratified by setting and ARI diagnosis

Parameter

Control group

PCT group

Measures of effect: adjusted OR or difference (95% CI), P value

P for interaction

Overall

3372

3336

Initiation of antibiotics, n (%)

2894 (86.3%)

2351 (71.5%)

0.27 (0.24 to 0.32), P < 0.001

Duration of antibiotics (days), mean (±SD)

9.4 ± 6.2

8.0 ± 6.5

‐1.83 (‐2.15 to ‐1.50), P < 0.001

Total exposure of antibiotics (days), mean (±SD)

8.1 ± 6.6

5.7 ± 6.6

‐2.43 (‐2.71 to ‐2.15), P < 0.001

Setting‐specific outcomes

Primary care

501

507

Initiation of antibiotics, n (%)

316 (63.1%)

116 (22.9%)

0.13 (0.09 to 0.18), P < 0.001

< 0.001

Duration of antibiotics (days), mean (±SD)

7.3 ± 2.5

7.0 ± 2.8

‐0.52 (‐1.07 to 0.04), P = 0.068

0.064

Total exposure of antibiotics (days), mean (±SD)

4.6 ± 4.1

1.6 ± 3.2

‐3.02 (‐3.45 to ‐2.58), P < 0.001

0.101

Emergency department

1638

1615

Initiation of antibiotics, n (%)

1354 (83.2%)

1119 (71.3%)

0.49 (0.41 to 0.58), P < 0.001

< 0.001

Duration of antibiotics (days), mean (±SD)

9.8 ± 5.4

7.3 ± 5.1

‐2.45 (‐2.86 to ‐2.05), P < 0.001

< 0.001

Total exposure of antibiotics (days), mean (±SD)

8.2 ± 6.2

5.2 ± 5.4

‐3.02 (‐3.41 to ‐2.62), P < 0.001

< 0.001

Intensive care unit

1233

1214

Initiation of antibiotics, n (%)

1224 (99.8%)

1116 (91.9%)

0.02 (0.01 to 0.05), P < 0.001

< 0.001

Duration of antibiotics (days), mean (±SD)

9.5 ± 7.4

8.8 ± 7.8

‐1.23 (‐1.82 to ‐0.65), P < 0.001

< 0.001

Total exposure of antibiotics (days), mean (±SD)

9.5 ± 7.4

8.1 ± 7.9

‐1.44 (‐1.99 to ‐0.88), P < 0.001

< 0.001

Disease‐specific outcomes

Community‐acquired pneumonia

1468

1442

Initiation of antibiotics, n (%)

1455 (99.4%)

1340 (92.9%)

0.08 (0.04 to 0.15), P < 0.001

< 0.001

Duration of antibiotics (days), mean (±SD)

10.5 ± 6.2

8.0 ± 5.7

‐2.45 (‐2.87 to ‐2.02), P < 0.001

< 0.001

Total exposure of antibiotics (days), mean (±SD)

10.4 ± 6.2

7.5 ± 5.9

‐2.94 (‐3.38 to ‐2.50), P < 0.001

0.004

Exacerbation of COPD

631

621

Initiation of antibiotics, n (%)

453 (71.8%)

266 (42.8%)

0.29 (0.23 to 0.36), P < 0.001

0.017

Duration of antibiotics (days), mean (±SD)

7.4 ± 5.3

7.2 ± 6.7

‐1.15 (‐2.00 to ‐0.31), P = 0.007

0.003

Total exposure of antibiotics (days), mean (±SD)

5.3 ± 5.6

3.1 ± 5.6

‐2.22 (‐2.83 to ‐1.60), P < 0.001

0.506

Acute bronchitis

287

257

Initiation of antibiotics, n (%)

189 (65.9%)

68 (26.5%)

0.18 (0.12 to 0.26), P < 0.001

< 0.001

Duration of antibiotics (days), mean (±SD)

7.1 ± 3.0

6.4 ± 3.5

‐0.35 (‐1.15 to 0.45), P = 0.393

0.359

Total exposure of antibiotics (days), mean (±SD)

4.7 ± 4.2

1.7 ± 3.3

‐2.95 (‐3.59 to ‐2.31), P < 0.001

0.33

Ventilator‐associated pneumonia

186

194

Initiation of antibiotics, n (%)

186 (100.0%)

193 (99.5%)

NA

NA

Duration of antibiotics (days), mean (±SD)

13.1 ± 7.9

10.8 ± 8.7

‐2.22 (‐3.80 to ‐0.65), P = 0.006

0.253

Total exposure of antibiotics (days), mean (±SD)

13.1 ± 7.9

10.8 ± 8.7

‐2.45 (‐4.09 to ‐0.82), P = 0.003

0.786

Note: Duration refers to the total days of antibiotic therapy in participants in whom antibiotics were initiated. Total exposure refers to the total days of antibiotic therapy in all randomised participants.

Measures of effect: dichotomous outcomes are reported as adjusted OR (95% CI) and continuous outcomes are adjusted mean differences and confidence intervals

ARI: acute respiratory infection
CI: confidence interval
COPD: chronic obstructive pulmonary disease
NA: not applicable
OR: odds ratio
PCT: procalcitonin
SD: standard deviation

Figuras y tablas -
Table 6. Antibiotic treatment overall and stratified by setting and ARI diagnosis
Comparison 1. Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at 30 days Show forest plot

32

10046

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.78, 1.01]

1.1 Primary care trials

2

1008

Odds Ratio (M‐H, Random, 95% CI)

0.32 [0.01, 7.98]

1.2 Emergency department trials

14

3805

Odds Ratio (M‐H, Random, 95% CI)

0.97 [0.70, 1.36]

1.3 Intensive care unit trials

16

5233

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.77, 1.00]

2 Treatment failure at 30 days Show forest plot

32

10046

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.81, 0.99]

2.1 Primary care trials

2

1008

Odds Ratio (M‐H, Random, 95% CI)

0.94 [0.72, 1.22]

2.2 Emergency department trials

14

3805

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.69, 1.05]

2.3 Intensive care unit trials

16

5233

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.81, 1.05]

Figuras y tablas -
Comparison 1. Procalcitonin algorithm versus no procalcitonin algorithm stratified by clinical setting
Comparison 2. Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality at 30 days stratified by adherence Show forest plot

32

10046

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.78, 1.01]

1.1 Adherence to procalcitonin algorithm > 70%

14

4422

Odds Ratio (M‐H, Random, 95% CI)

1.05 [0.81, 1.37]

1.2 Adherence to procalcitonin algorithm < 70% or not available

18

5624

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.73, 0.97]

2 Treatment failure at 30 days stratified by adherence Show forest plot

32

10046

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.81, 0.99]

2.1 Adherence to procalcitonin algorithm > 70%

14

4422

Odds Ratio (M‐H, Random, 95% CI)

0.87 [0.75, 1.02]

2.2 Adherence to procalcitonin algorithm < 70% or not available

18

5624

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.81, 1.04]

3 Mortality at 30 days stratified by allocation concealment Show forest plot

32

10046

Odds Ratio (M‐H, Random, 95% CI)

0.89 [0.78, 1.01]

3.1 Trials with concealed allocation

22

7968

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.76, 1.01]

3.2 Trials without concealed allocation

10

2078

Odds Ratio (M‐H, Random, 95% CI)

0.95 [0.70, 1.28]

4 Treatment failure at 30 days stratified by allocation concealment Show forest plot

32

10046

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.81, 0.99]

4.1 Trials with concealed allocation

22

7968

Odds Ratio (M‐H, Random, 95% CI)

0.91 [0.82, 1.02]

4.2 Trials without concealed allocation

10

2078

Odds Ratio (M‐H, Random, 95% CI)

0.82 [0.64, 1.04]

5 Mortality at 30 days stratified by blinded outcome assessment Show forest plot

32

10046

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.78, 1.00]

5.1 Trials with blinded outcome assessment

9

4664

Odds Ratio (M‐H, Fixed, 95% CI)

1.05 [0.84, 1.32]

5.2 Trials without blinded outcome assessment

23

5382

Odds Ratio (M‐H, Fixed, 95% CI)

0.82 [0.70, 0.95]

6 Treatment failure at 30 days stratified by blinded outcome assessment Show forest plot

32

10046

Odds Ratio (M‐H, Fixed, 95% CI)

0.90 [0.81, 0.99]

6.1 Trials with blinded outcome assessment

9

4664

Odds Ratio (M‐H, Fixed, 95% CI)

0.92 [0.79, 1.06]

6.2 Trials without blinded outcome assessment

23

5382

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.77, 1.01]

7 Mortality at 30 days stratified by follow up Show forest plot

32

10046

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.78, 1.00]

7.1 Trials with 1 month follow up for mortality

18

7337

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.74, 0.98]

7.2 Trials with different follow up for mortality

14

2709

Odds Ratio (M‐H, Fixed, 95% CI)

1.01 [0.78, 1.30]

Figuras y tablas -
Comparison 2. Procalcitonin algorithm versus no procalcitonin algorithm, sensitivity analyses