Open Access

Role of biomarkers in the management of antibiotic therapy: an expert panel review II: clinical use of biomarkers for initiation or discontinuation of antibiotic therapy

  • Jean-Pierre Quenot1, 2,
  • Charles-Edouard Luyt3,
  • Nicolas Roche4,
  • Martin Chalumeau5, 6,
  • Pierre-Emmanuel Charles1, 7,
  • Yann-Eric Claessens8,
  • Sigismond Lasocki9,
  • Jean-Pierre Bedos10,
  • Yves Péan11,
  • François Philippart12,
  • Stéphanie Ruiz13,
  • Christele Gras-Leguen14,
  • Anne-Marie Dupuy15,
  • Jérôme Pugin16,
  • Jean-Paul Stahl17,
  • Benoit Misset12, 18,
  • Rémy Gauzit19 and
  • Christian Brun-Buisson20, 21Email author
Annals of Intensive Care20133:21

DOI: 10.1186/2110-5820-3-21

Received: 15 May 2013

Accepted: 8 June 2013

Published: 8 July 2013

Abstract

Biomarker-guided initiation of antibiotic therapy has been studied in four conditions: acute pancreatitis, lower respiratory tract infection (LRTI), meningitis, and sepsis in the ICU. In pancreatitis with suspected infected necrosis, initiating antibiotics best relies on fine-needle aspiration and demonstration of infected material. We suggest that PCT be measured to help predict infection; however, available data are insufficient to decide on initiating antibiotics based on PCT levels. In adult patients suspected of community-acquired LRTI, we suggest withholding antibiotic therapy when the serum PCT level is low (<0.25 ng/mL); in patients having nosocomial LRTI, data are insufficient to recommend initiating therapy based on a single PCT level or even repeated measurements. For children with suspected bacterial meningitis, we recommend using a decision rule as an aid to therapeutic decisions, such as the Bacterial Meningitis Score or the Meningitest®; a single PCT level ≥0.5 ng/mL also may be used, but false-negatives may occur. In adults with suspected bacterial meningitis, we suggest integrating serum PCT measurements in a clinical decision rule to help distinguish between viral and bacterial meningitis, using a 0.5 ng/mL threshold. For ICU patients suspected of community-acquired infection, we do not recommend using a threshold serum PCT value to help the decision to initiate antibiotic therapy; data are insufficient to recommend using PCT serum kinetics for the decision to initiate antibiotic therapy in patients suspected of ICU-acquired infection. In children, CRP can probably be used to help discontinue therapy, although the evidence is limited. In adults, antibiotic discontinuation can be based on an algorithm using repeated PCT measurements. In non-immunocompromised out- or in- patients treated for RTI, antibiotics can be discontinued if the PCT level at day 3 is < 0.25 ng/mL or has decreased by >80-90%, whether or not microbiological documentation has been obtained. For ICU patients who have nonbacteremic sepsis from a known site of infection, antibiotics can be stopped if the PCT level at day 3 is < 0.5 ng/mL or has decreased by >80% relative to the highest level recorded, irrespective of the severity of the infectious episode; in bacteremic patients, a minimal duration of therapy of 5 days is recommended.

Keywords

Infection Sepsis Emergency medicine Biomarkers Procalcitonin C-reactive protein Pancreatitis Meningitis Pneumonia

Biomarkers and initiation of antibiotic therapy

According to the preset selection criteria (see part I), the panel reviewed four conditions in which the potential clinical role of biomarkers has been studied: acute pancreatitis, respiratory tract infections, meningitis, and sepsis in the ICU.

Acute pancreatitis in adults

The clinical presentation and severity of patients having acute pancreatitis varies considerably, from a mild abdominal discomfort to multiple organ failure and death. The potential role of biomarkers in this condition should thus be twofold: 1) a prognostic value, to help define the most appropriate therapeutic approach, by predicting the severity of the disease and accurately select those patients needing close monitoring in the ICU; and 2) a diagnostic value, to help identify those patients having infected pancreatic necrosis, who might need drainage or surgery. Mofidi et al. [1] have recently reviewed the potential role of PCT in answering these two questions, by analysing 12 observational studies [2-9] totalling 956 patients. The threshold PCT value used in these studies to predict the severity of pancreatitis varied from 0.25 to 1.8 mg/L, with an associated combined sensitivity of 0.72 (0.65-0.78), a specificity of 0.86 (0.83-0.89), and an area under the receiver operating curve (AUROC) of 0.87. In the seven studies (n = 264 patients) examining the value of PCT for predicting the presence of infected necrosis [25, 79], the threshold value varied across studies between 0.48 and 3.5 mg/L, with an associated sensitivity of 0.8 (0.71-0.88), a specificity of 0.91 (0.87-0.94), and an AUROC of 0.91 (Table 1). In these seven studies, PCT levels were confronted to microbiological results obtained from fine-needle biopsy and culture of intra-abdominal collections, taken as the “gold standard.”
Table 1

Use of biomarkers for the diagnosis of infected necrosis secondary to acute pancreatitis

Marker

Study

Study design

Nb of patients, n

Level of evidence

Biomarker tested and groups compared

Main results

1 st author, [Ref]

PCT/CRP

Rau B, [2]

Observational

61

Low

Comparison of PCT and CRP levels between 3 groups:

AUROC for the diagnosis of infected necrosis:

Oedematous pancreatitis (n = 22)

PCT (>1.8 mg/L) = 0.95 (Se: 95%, Sp: 88%),

Sterile necrosis (n = 18)

CRP (>300 mg/L) = 0.86 (Se:86%, Sp: 75%); p < 0.02

Infected necrosis (n = 21) according to imaging/surgery/microbiological data

PCT/CRP/GCSF

Muller CA, [3]

Observational

64

Low

Comparison of PCT, G-CSF, and CRP between patients having oedematous pancreatitis (n = 29)

AUROC for diagnosing infected necrosis:

CRP (>250) = 0.79 (Se: 83, Sp: 70%), PCT (0.45) = 0.77 (Se: 92%, Sp: 65%), AUC G-CSF (101) = 0.72 (Se: 92%, Sp: 48%)

Noninfected necrosis (n = 23)

Infected necrosis (n = 12) according to imaging/surgery/microbiological data

PCT/CRP/IL8

Rau B, [4]

Observational

50

Low

Comparison of PCT, IL8, and CRP levels between patients with:

AUROC for diagnosing infected necrosis:

Oedematous pancreatitis (n = 18)

CRP (>300) = 0.84 (Se: 83, Sp: 78%),

Non-infected necrosis (n = 14)

PCT (>1.8) = 0.97 (Se: 94%, Sp: 90%)

Infected necrosis (n = 18) according to imaging/surgery/microbiological data

IL-8 (112) = 0.78 (Se: 72%, Sp: 75%)

PCT/CRP/IL6/TNF

Riche F, [5]

Observational

48

Low

Comparison of PCT, IL-6, TNF-α, and CRP between patients having

AUROC for diagnosing infected necrosis:

- Noninfected necrosis (n = 33)

CRP = 0.76,

- Infected necrosis (n = 15), according to imaging/surgery/microbiological data

PCT = 0.78,

IL 6 = 0.77,

TNF α = 0.5

PCT

Purkayastha S, [6]

Literature review (5 studies)

206

Low

Assessing the value of PCT for diagnosing infected pancreatic necrosis

Threshold values for PCT vary from 0.48 to 2;

Sensitivity: 0.73 to 0.94

Specificity: 0.65 to 1

PCT/IL6/TNF/sTREM1

Lu Z, [7]

Observational

30

Low

Comparison of PCT, IL-6, TNF-α, and sTREM-1 levels in serum and drainage fluid between patients having:

Biomarker levels in drainage fluid: No difference between the two groups for CRP, TNF-α, and IL-6 levels

- Noninfected necrosis (n = 12), or

- sTREM1 (287), AUC = 0.97 (Se = 94, Sp = 92)

- Infected necrosis (n = 18), according to imaging/surgery/microbiological data

- PCT (2.1): AUC = 0.9 (Se = 86, Sp = 91).

Lower AUCs for serum levels:

PCT: 0.79; sTREM1: 0.73

PCT

Olah A, [8]

Observational

24

Low

Comparison of PCT levels in patients having

Serum PCT level >0.5 predicts infected necrosis with Se = 75% and Sp = 83%.

- Noninfected necrosis (n = 12)

Fine-needle aspiration predicts infection with Se = 92% and Sp = 100%.

- Infected necrosis (n = 12)

According to results of fine-needle aspiration and culture and surgery

PCT/IL6/sICAM1

Mandi Y, [9]

Observational

30

Low

Comparison of PCT, IL-6, and sICAM-1 between patients with

Only PCT (threshold >1 mg/L) allowed to distinguish patients with or without infected necrosis (Se = 90%; Sp = 100%).

Noninfected necrosis (n = 10)

Infected necrosis (n = 10), according to results of biopsy and culture.

PCT

Mofidi R, [1]

Literature review (7 studies)

264

Low

Assessment of PCT serum levels for the diagnosis of infected pancreatic necrosis

Threshold values vary from 0.48 to 3.5 mg/L, with a sensitivity of 0.63 to 0.92 and specificity of 0.71 to 0.97.

Summary table: infected necrosis in acute pancreatitis

Number of studies, n

Total number of patients, n

Highest level of evidence

Directness*

Consistency of results**

Overall strength of evidence

7

264a

Low

Yes

 

Yes

Moderate

aNumber of patients included in diagnostic studies of infected pancreatic necrosis.

*Directness: studies provide evidence of a direct association between a treatment or a given risk factor and a judgment criterion.

**Consistency: results from studies of similar level of evidence are not contradictory.

Other less commonly measured biomarkers (IL-6, IL-8, sTREM-1, TNF-α) also have been compared to PCT for their ability to help answer the two questions above. These biomarkers provided AUROC comparable to those of PCT, both in terms of prognostic value and of diagnosis of infected necrosis [2, 46, 9, 10]. Conversely, CRP levels appear less discriminatory for the prediction of infected necrosis [2]. No study has evaluated the value of repeated PCT measurements to predict infection, and no study has evaluated the impact on patients’ outcome of the initiation of antibiotic therapy guided by a biomarker level in patients suspected of infected necrosis.

In summary, we suggest that PCT be measured to help predict infection in patients suspected of infected necrosis during acute pancreatitis; it is however difficult from the available literature to define a precise threshold value (0.5-1.0 mg/L). A PCT value above the threshold might reinforce the clinician’s judgment that a fine-needle aspiration and culture is needed to confirm infection, while a value below this threshold might help deferring this intervention and proceed with watchful waiting. There is insufficient data to recommend initiating antibiotic therapy based on biomarker levels: this decision is based on a careful repeated evaluation of the patient and on the results of fine-needle aspiration material, which currently remains the cornerstone for the decision to initiate or maintain antibiotic therapy.

Lower respiratory tract infection in adults

Antibiotics often are prescribed in excess to patients having a clinical syndrome of community-acquired lower respiratory tract infection (LRTI). Despite the usually viral aetiology of their illness, an estimated 75% of patients with acute bronchitis receive antibiotics [11]; indeed, clinical presentation does not allow the distinction between bacterial and viral infection, which encourages physicians to err on the “safe side” and prescribe antibiotics. Communication campaigns inciting primary physicians to limit unnecessary prescriptions for LRTI have a moderate impact, which is difficult to maintain over time [12, 13]. In this context, the addition of biomarker measurements to the clinical evaluation of such patients may have two main potential effects: improve the diagnostic accuracy, and reassure the patient and the physician that antibiotic therapy is unnecessary.

An abundant literature is available on PCT-guided initiation of antibiotic therapy in patients suspected clinically of having LRTI, providing a high-level of evidence. To date, 11 randomised, controlled studies using a similar approach have been published and provide consistent results [1425]. All these studies have used a similar algorithm [2629] to help decide on the initiation and continuation of antibiotic therapy, with a lower PCT threshold of <0.25 ng/mL to encourage physicians to withhold antibiotic prescription. The absolute risk reduction of antibiotic administration varies between 11% and 72% across these studies compared with “usual care” based on local recommendations and physicians’ judgment and preferences (Table 2). In one study, however, antibiotic prescriptions increased by 6% with PCT-guided therapy [19]. It also should be noted that the 0.25 ng/mL threshold may be less reliable in the elderly, where an 8% false-positive rate has been reported [30].
Table 2

Role of biomarkers in the initiation of antibiotic therapy for lower respiratory tract infection

Biomarker

Study (ref)

Study design

Nb patients, n (setting)

Level of evidence

End-point

Main results, absolute risk reduction (ARR) or odds ratio (OR; 95% CI)

 

1 st author, [Ref]

     

PCT

Stolz D, [20]

Single-centre, randomised, controlled open study

208

High

Antibiotic exposure and rate of initiation of antibiotic therapy, based on PCT level > 0.25 μg/L

ARR = 32% (40% vs. 72%) of antibiotic prescriptions in the PCT-guided group.

   

(AECB)

   
      

Ab exposure OR = 0.56 [0.43-0.73]

PCT

Schuetz P, [25]

Multicentre, open RCT

1359

High

Antibiotic exposure

ARR = 12% (75.4% vs. 87.7%) in PCT group, Overall antibiotic exposure = - 35% (5.7 vs. 8.7 days).

  

Noninferiority study

(ED)

 

Based on a PCT level > 0.25 μg/L for initiating prescription.

 

PCT

Christ-Crain M, [18]

Single-centre open RCT

302

High

Antibiotic initiation rate

ARR = 14% (85% vs. 99%) in initial antibiotic prescription in PCT group

   

(ED, ward)

 

Antibiotic exposure

 
     

Based on a PCT level > 0.25 μg/L to initiate therapy

Overall ab exposure: OR = 0.52 [0.48–0.55]

PCT

Kristoffersen KB, [19]

Single-centre, open, RCT

210

High

Antibiotic prescription rate, based on a PCT level > 0.25 μg/L to initiate therapy in PCT group

3% increase in antibiotic prescription (88% vs. 85%) in the PCT group

   

(ED, ward)

   

PCT

Long W, [23]

Single-centre, open RCT

127

High

Antibiotic prescription rate, based on a PCT level > 0.25 μg/L in the PCT group

ARR = 11% of antibiotic prescriptions in the PCT group

   

(ED)

   

PCT

Long W, [22]

Single-centre, open RCT

156

High

Antibiotic prescription rate, based on a PCT level > 0.25 μg/L in the PCT group

ARR = 13% of antibiotic prescriptions in the PCT group

   

(ED)

   

PCT

Burkhardt O, [16]

Single-centre, open RCT, noninferiority

550

High

Antibiotic prescription rate, based on a PCT level > 0.25 μg/L in the PCT group

ARR = 15% (21.5% vs. 36.7%) for antibiotic prescription rate in the PCT group

   

(PC)

   

PCT

Briel M, [15]

Multicentre, open RCT, noninferiority

458

High

Antibiotic prescription rate, based on a PCT level > 0.25 μg/L in the PCT group

ARR = 72% [95% CI 66-78] for antibiotic prescription rate in the PCT group

   

(PC)

   

PCT

Schuetz P, [30]

Meta-analysis of 14 RCTs

3 119

High

 

Risk reduction of initial antibiotic therapy: OR = 0.24 (95% CI, 0.2-0.29)

      

Overall antibiotic exposure:

      

OR = 0.1 (95% CI = 0.07-0.14), without difference in mortality rates

PCT

Van der Meer V, [28]

Literature review on the use of CRP (13 studies)

13

High

Prediction of LRTI

Bacterial LRTI predicted with a sensitivity varying from 8% to 99% and a specificity varying from 27% to 95%

PCT

Schuetz P, [29]

Review of 8 RCTs using an PCT-based algorithm for the initiation of antibiotic therapy

3 457

High

Antibiotic prescription rate

ARR varying from 6% to 72%

CRP

Cals JW, [24]

Multicentre, open cluster-RCT, testing a CRP-based algorithm

431

High

Antibiotic prescription rate and antibiotic exposure, based on a CRP value < 20 : no antibiotic; CRP >100 : atb recommended, and 20<CRP<99 : reassess for possible therapy

ARR = 22% (31% vs. 53%) of initial antibiotic prescriptions in the CRP group

      

Overall antibiotic exposure: - 13% (45% vs. 58%)

PCT

Christ-Crain M, [17]

Multicentre, open, cluster-RCT

243

High

Antibiotic prescription rate, based on a PCT level > 0.25 μg/L in the PCT group

ARR = 39% for antibiotic prescription rate in the PCT group

   

(ED)

   

Summary of evidence table: Lower respiratory tract infection

Number of studies, n

Total number of patients, n

Highest level of evidence

Directness*

Consistency**

Overall strength of evidence

12

4 412

High

Yes

Yes

Strong

*Directness: studies provide evidence of a direct association between a treatment or a given risk factor and a judgment criterion.

**Consistency: results from studies of similar level of evidence are not contradictory.

Among the 14 studies of PCT-guided therapy for LRTI reviewed by the Cochrane Collaboration [31, 32], only 3 enrolled patients with a nosocomial infection (hospital-acquired or ventilator-associated) [3335], 2 of which evaluated the impact of PCT-guided therapy on the initiation of treatment [33, 34]. However, nosocomial acquisition of infection is identifiable only in the study by Bouadma et al. [33], and only 5% (n = 141) of all patients enrolled fulfilled this criteria; nearly all patients in this subgroup were administered antibiotics (99% in the PCT-guided therapy group and 100% in controls). Repeated measurements might be helpful for initiating antibiotics in this subgroup; however, the few data available on a limited number of patients (n = 89 patients) [36] do not allow making a recommendation in this regard.

In summary, we suggest withholding antibiotic therapy in adult patients suspected of community-acquired LRTI and having a serum PCT level <0.25 ng/mL; if clinical suspicion is high, it is however recommended to repeat the PCT measurement at a 6-h interval and reassess the therapeutic approach, accounting for new clinical findings. In patients having nosocomial LRTI, data are insufficient to recommend tailoring the therapeutic approach based on a single PCT level or even repeated measurements.

Meningitis

Childhood meningitis

Most acute meningitis in children is of viral aetiology and evolves favourably [37, 38]. Despite their relatively low prevalence, acute bacterial meningitis are severe infections, often resulting in debilitating sequels or even death [39]; thus, antibiotic therapy is recommended in children presenting with acute meningitis, at least until cerebrospinal fluid (CSF) cultures are available, i.e., within the first 48–72 h [40]. The risk-benefit ratio and costs associated with this prudent approach is likely unfavourable, because it involves numerous unnecessary hospitalisations, increased costs, and side effects of treatments, including selection of resistant organisms [41]. Biomarkers might help to reduce these unwanted effects [42, 43]. Ideally, a good biomarker would have 100% sensitivity for the diagnosis of bacterial meningitis, together with an acceptable specificity [38]; however, when used alone, available biomarkers (PCT, CRP, IFN-Υ, etc.) have sensitivities and specificities that do not appear high enough to base a therapeutic decision on their results given the risks incurred in case of a false-negative test [44, 45].

To overcome this problem, several groups have proposed decision rules combining clinical criteria and biomarker results [4650]. The Bacterial Meningitis Score (BMS) [46] has been reported to have 100% sensitivity and 67% specificity for the detection of bacterial meningitis and is easily applicable at the bedside. This decision rule encourages ambulatory treatment of children having meningitis (i.e., a CSF leucocytes count ≥7/mm3) if none of the following five criteria is present: seizures, blood polymorphonuclear (PMN) cells count ≥10,000/mm3, direct examination of CSF positive, CSF protein level ≥0.8 g/L, or CSF PMN ≥1000/mm3. The BMS has undergone external validation on the large database of the French national registry for childhood bacterial meningitis (ACTIV-GPIP) [51]. Of 889 children with confirmed bacterial meningitis, 884 were correctly identified by the BMS rule (sensitivity = 99.6%; 95% confidence interval (CI) 98.9-99.8) with a specificity >60%. Thus, despite these near-perfect results, a few patients with bacterial meningitis (n = 5) were not detected by the BMS [52]; that the BMS can have a few false-negatives also was confirmed by a recent meta-analysis [53]. The Meningitest® (European patent EP1977244) has been subsequently proposed to refine the BMS and avoid these false-negatives, by omitting some variables of poor discriminatory power and introducing the serum PCT level [45, 54]. The Meningitest® rule suggests initiating antibiotic therapy if at least one of the following criteria is present: seizures, toxic appearance, purpura, PCT level ≥0.5 ng/mL, positive CSF Gram stain, or CSF protein level ≥0.5 g/L. External validation of the Meningitest® has been performed on an European database of 198 patients (including 96 with bacterial meningitis), where its sensitivity and specificity were respectively of 100% (95% CI 96–100) and 36% (95% CI 27–46) for the diagnosis of bacterial meningitis, whereas corresponding values for the BMS were 100% (95% CI 96–100) and 52% (95% CI 42–62) [55]. A single serum PCT level ≥0.5 ng/mL has similar sensitivity and specificity as the BMS, whereas combining CRP with CSF protein levels provided lower performances.

In summary, for children with suspected bacterial meningitis, we recommend using a decision rule as an aid to triage decisions and antibiotic prescribing, such as the BMS (more specific, but with a few false-negatives) or the Meningitest® (less specific, but no false-negative described to date). A single PCT level ≥0.5 ng/mL also may be used, but false-negatives may occur.

Adult meningitis

The potential role of biomarkers in the management of meningitis has been much less studied in adults than in children. Similarly to children, the use of a clinical decision rule to distinguish between viral and bacterial meningitis is recommended in adults [56]. For example, the French 2008 consensus conference on meningitis recommended using one of three decision rules: the rule developed by Hoen et al. [57], the BMS, or the Meningitest® [56]. It should be noted that the former rule has insufficient sensitivity in children (94%), with a risk of false-negatives [45].

Knudsen et al. have examined the impact of various biomarkers in the diagnostic workup of 55 adult patients with meningitis [58]. These authors found an AUROC of 0.91, 0.87, and 0.72 for CRP, PCT, and sCD 163, respectively, and concluded that CRP and PCT levels could be useful when combined with results of CSF examination to help diagnose bacterial meningitis. One recent study [59] included 151 patients admitted to an adult emergency department with suspected of bacterial meningitis and a negative direct examination of CSF, to assess the diagnostic value of CRP, PCT, and CSF leucocytes count. The AUROC of PCT and CRP were 0.98 (95% CI, 0.83-1.0) and 0.81 (95% CI, 0.58-0.92), respectively; however, the small number of patients with confirmed bacterial meningitis (n = 18) limits the inferences from this study. Of note, the CSF leucocytes count appeared to have little discriminatory value (AUC = 0.59) in that study. In another study of 30 patients (including 16 having bacterial meningitis), Schwarz et al. [60] found that PCT had a sensitivity of 69% and a specificity of 100% for diagnosing bacterial meningitis. In another larger prospective study that included 112 adult patients admitted to the hospital for meningitis (90 viral and 22 bacterial), Viallon et al. [61] found that a serum PCT value >0.93 ng/ml was 100% sensitive for the diagnosis of bacterial meningitis; conversely, a CSF lactate level <3.2 mmoles/L had a 100% NPV (Table 3). Low CRP levels have high NPV, but have not been shown to contribute markedly to the diagnostic approach [62]. The 2008 French consensus conference on management of acute bacterial meningitis [56] concluded that these biomarkers could be helpful for diagnosing bacterial meningitis in adults, pointing out that a threshold value for serum PCT of 0.5 ng/mL had a high sensitivity (99%; 95% CI, 97–100) and specificity (83%; 95% CI, 76–90), and that bacterial meningitis could be considered very unlikely when PCT was <0.5 ng/mL or CSF lactate was below 3 mmoles/L.
Table 3

Studies of biomarkers in the diagnosis of bacterial meningitis (BM) and its distinction from viral meningitis (VM)

Marker

Study 1st author, [ref]

Study design

Number of patients, n

Level of evidence

End-point

Main result

      

Absolute risk reduction (RR)

PCT

Gendrel D, [42]

Single-centre observational study

59 children (18 BM, 41 VM)

Very low

Comparison of PCT and CRP level in patients with bacterial or viral meningitis

A serum PCT level >0.5 μg/L is associated with bacterial meningitis (Se = 94%; Sp = 100%).

      

Large overlap for CRP values

PCT/CRP/INF-ϒ

Marc E, [43]

Single-centre observational study

58 viral

Very low

Antibiotic initiation and hospital days, based on a serum PCT < 0.5 to not initiate or stop antibiotics. If PCT >0.5, antibiotics stopped if negative cultures and/or INF or PCR (+) in CSF

41 patients did not receive antibiotics; antibiotics stopped in 15/17 pts treated by day 1 or 2, because of a PCT < 0.5.

   

(enterovirus outbreak)

   
   

Children (2 mo – 14 yr)

   
      

Hospital days reduced to 2 days.

PCT/CRP/sCD 163

Knudsen T, [58]

Single-centre observational study (ID department)

55 adult patients suspected of BM

Very low

Comparison of PCT, CRP and sCD163 levels in patients with bacterial or viral meningitis, or other infection

Diagnostic value of CRP (AUC = 0.91) and PCT (AUC = 0.87) superior (p < 0.02 and p < 0.06) to sCD163 (AUC = 0.72);

      

sCD163 most specific for systemic bacterial infection (Sp = 0.91).

PCT/CRP

Viallon A [61]

Single-centre observational study

254 adults (183 VM, 97 BM)

Low

Predictive value of serum PCT and CRP for the diagnosis of BM

AUROC PCT = 0.86; threshold 0.28 μg/mL (Se = 0.97; Sp = 1, VPP = 0.97, VPN = 1)

      

AUROC CRP = 0.92; threshold 37 mg/L (Se = 0.86, Sp = 0.84, VPP = 0.46, VPN = 0.97)

CRP

Gerdes L, [62]

Meta analysis of 10 studies

Children and adults

low

Predictive value of serum CRP for bacterial meningitis

Threshold value for CRP varies across studies from 19 to 100 mg/l.

      

Se varies from 92% to 94% and NPV is >97%.

Summary table

 

Total number of patients

Highest level of evidence

Directness*

Consistency of results**

Overall strength of evidence

Number of studies

 

371

Low

Yes

Yes

Low

3 (PCT)

*Directness: studies provide evidence of a direct association between a treatment or a given risk factor and a judgment criterion.

**Consistency: results from studies of similar level of evidence are not contradictory.

In summary, we suggest integrating serum PCT measurements in a clinical decision rule for meningitis in adults to help distinguish between viral and bacterial meningitis, using a threshold of 0.5 ng/mL.

Adult intensive care patients

Most controlled studies performed in intensive care patients have examined the value of biomarkers to limit the duration of antibiotic therapy, and few have concentrated on its initiation. Although a recent meta-analysis suggests that PCT is helpful for differentiating sepsis from SIRS [63], the initiation of antibiotic therapy in ICU patients has been assessed in only two randomised open studies testing a PCT-based algorithm (Table 4) [33, 34]. In the study by Layios et al. [34], there was no difference in the rate of initiation of therapy between the control group and the PCT-based group (where antibiotics were strongly discouraged if PCT was lower than 0.25 ng/mL, and strongly encouraged if PCT was higher than 1 ng/mL). In the multicentre study performed by Bouadma et al. [33] and using a similar algorithm, the risk reduction of initiating antibiotic therapy varied between 5% and 13% across centres. However, the small number of patients having CAP (n = 69) and the very low observance of the algorithm for withholding antibiotics when PCT levels were low (6%) in this study do not allow concluding on this point.
Table 4

Biomarkers and initiation or discontinuation of antibiotic therapy in adult ICU patients with sepsis

Biomarker

Study 1st author, year [ref]

Study design, patient selection (objective)

Nb of patients n

Level of evidence

Primary endpoint and protocol

Main results PCT-guided vs. controls (ARR, absolute risk reduction)

PCT

Layios N, [34]

Open, randomised controlled trial, 5 ICUs

509

High

Total antibiotic use in ICU patients when using a PCT-based algorithm for initiating antibiotics (lower PCT threshold for not initiating therapy: 0.25 ng/mL)

Percent days on antibiotics or overall DDD did not differ between the two groups. Withholding or withdrawing antibiotics similar overall (ARR = 3%) and with low PCT levels (PCT: 46.3%; controls: 32.7%; p = NS), or higher levels.

  

Patients suspected of infection on admission or during the ICU stay (initiation of therapy)

PCT: 353

   
   

Ctr: 314

   

PCT

Nobre V, [35]

Single-centre, open RCT;

79

Moderate

Total antibiotic days.

ARR antibiotic days: 3.5 (6 vs. 9.5 days; p = 0.15),

  

PCT-guided withdrawing antibiotics vs. “standard care” (duration)ICU patients with severe sepsis/shock on admission or during ICU stay (excl. immunosuppressed patient or requiring prolonged therapy)

PCT: 39 (31 assessed)*

 

Recommend stopping antibiotics if PCT levels ≤ 90% of initial value but not before Day 3 (if baseline PCT level <1 ng/mL) or Day 5 (if baseline level ≥ 1 ng/mL).

Less overall ab exposure (504 vs. 655 ab days; p = 0.28); days alive without antibiotics at 28 days (15.3 vs. 13.3 days; p = 0.28). 28-d mortality: 20.5% vs. 20%

   

Ctr: 40 (37 assessed)*

   
   

70% CA infections

  

*4 and 2 secondary exclusions for complicated infections (empyema, mastoiditis, abscess)

PCT

Bouadma L, [33]

Multicenter randomised open trial, 7 ICUs

630

High

Number of days alive and without antibiotics; noninferiority in terms of mortality by using a PCT-based algorithm for initiating or withdrawing antibiotics in those suspected of infection on admission or during the ICU stay (lower PCT threshold for not initiating or stopping therapy: 0.25 ng/mL)

ARR: 5% for initiating antibiotics (PCT: 91% vs. 96% in Ctr group).

  

Sepsis in ICU patients, on admission or ICU-acquired (Initiation and duration)

PCT: 311

   
   

Ctr: 319

  

ARR for nb of antibiotic days: 2.7 days [1.4–4.1]

      

Ab-free days by 28 d: 11.6 vs. 14.3 days

      

28-d mortality : 21.2% vs. 20.4%; ARR = 0.8% [-4.6 to 6.2]

PCT

Stolz D, [69]

Multicentre open randomised trial, 7 ICUs (duration of therapy for VAP)

101

Moderate

Ab-free days alive at 28 days

Ab-free days at 28 d: 13 vs. 9.5 days

   

PCT: 51

 

Discontinue ab if PCT <0.25 or <0.5 ng/ml and decrease by >80% from initial level

Ab duration: 10 vs. 15 days

   

Ctr: 50

  

28-d mortality: 20% vs. 28%

PCT

Hochreiter M, [70]

Single-centre open randomised trial

110

Moderate

Reduction in ab duration

Mean Ab duration: 5.9 vs. 7.9 d

  

Postoperative sepsis (duration)

PCT: 57

 

Discontinue ab if PCT <1.0 and clinical improvement, or sustained decrease to 25-35% initial value for 3 days

Mean ICU LOS:

   

Ctr: 53

  

28-dMortality: 26.3% vs. 26.4%

PCT

Kopterides P, [71]

Meta-analysis of RCT in ICU patients (7 studies)

1131 patients

High

Various algorithms for discontinuation of Ab therapy

Duration ab : -2.1 [-2.5 to – 1.8] d

      

Total Ab exposure: -4.2 [-5 to -3.4] days

      

Ab free-days: 2.9 [1.9–3.9] days

      

28-d mortality: OR = 0.93 [0.69-1.26]

Summary table: Sepsis in ICU patients

 

Total number of patients, n

Highest level of evidence

Directness*

Consistency**

Overall strength of evidence

Number of studies, n

 

1010

High

Yes

Yes

Initiation of therapy: low

7

     

Discontinuation of therapy: high

 

*Directness: studies provide evidence of a direct association between a treatment or a given risk factor and a judgment criterion.

**Consistency: results from studies of similar level of evidence are not contradictory.

Relying on changes in PCT levels might be helpful for the initiation of antibiotic therapy in intensive care patients suspected of ICU-acquired infection; however, currently available data (on a total of 207 patients) are insufficient to base a recommendation on these [36, 64]. One randomized, controlled study that enrolled 604 ICU patients has tested the diagnostic value of daily measurements of serum PCT levels (using a threshold of 1 ng/mL to rapidly initiate a diagnostic workup and protocolised therapy) [65]. The length of ICU stay and of mechanical ventilation were actually higher in the PCT arm (without difference in 28-day mortality), and time to adequate therapy was not lower (except for patients with bacteremia). Of note, antibiotic consumption was significantly higher in the PCT arm, as well as the total number of days spent in the ICU with three or more antibiotics.

In summary, we do not recommend using a threshold serum PCT value to help in the decision to initiate antibiotic therapy in ICU patients suspected of community-acquired pneumonia. There are insufficient data available to recommend using repeated PCT measurements and serum kinetics for the decision to initiate antibiotic therapy in ICU patients suspected of ICU-acquired infection.

When can biomarkers help the decision to stop antibiotic therapy?

Given the number of studies examining this question and the high level of evidence generated, investigating this question was limited to examining randomized, controlled studies having tested a strategy based on biomarker measurement(s), to the exclusion of all other study designs. All studies in hospitalised patients used serum PCT level measurements, as there is no study testing the impact of using another biomarker in this specific indication; whereas several studies have tested the value of CRP for initiating antibiotics in pre-hospital care [24, 6668], none examined its potential impact on discontinuation of antibiotics, although several studies are ongoing (see http://www.clinicaltrials.gov/ct2/results?term=c+reactive+protein+and+duration&recr=&rslt=&type=&cond=&intr=&outc=&spons=&lead=&id=&state1=&cntry1=&state2=&cntry2=&state3=&cntry3=&locn=&gndr=&rcv_s=&rcv_e=&lup_s=&lup_e=). Accordingly, only studies using PCT levels are considered below.

How can biomarkers be used to help decide on discontinuing antibiotic treatment?

To date, 14 trials have examined the clinical impact of PCT-guided antibiotic therapy and its discontinuation [1520, 22, 23, 33, 35, 69, 70, 72],[73]. Nine of these focused on the latter objective; four were conducted in prehospital care or emergency room, whereas the remaining five were conducted in ICU patients. Although specific stopping rules may vary across trials and population enrolled, all studies used a PCT-based algorithm to help decide on stopping antibiotics (Table 5).
Table 5

PCT-based algorithms used for discontinuing antibiotic therapy in randomized, clinical trials

Author [ref], acronym

Setting

Population

Number of patients

Algorithm used

Emergency department and ambulatory care

Christ-Crain [18], ProCAP trial

Emergency room

CAP

302

PCT measured d4, d6, d8

- 151 PCT-guided arm

Stopping antibiotics encouraged if PCT < 0.25μg/L; strongly encouraged if PCT < 0.1 μg/L

- 151 control arm

If initial PCT >10μg/L, stop when decreased by ≥90%

Briel [15]

Ambulatory care

Lower RTI

458

PCT at d3

- 232 PCT-guided arm

Encourage stopping if PCT d3 ≤ 0.25 μg/L

- 226 control arm

Schuetz [25]

Emergency room

Upper & lower RTI

1359

PCT at d3, d5, d7 if patient still hospitalised

- 671 PCT-guided arm

Stop antibiotics when PCT ≤ 0.25 μg/L

If initial PCT >10 μg/L, stop when decreased by ≥80%

- 688 control arm

Long W [22]

Emergency room

CAP

172

PCT at d1, d3, d6, & d8

- 86 PCT-guided arm

Stop when PCT ≤ 0.25 μg/L

- 86 control arm

Intensive care unit

Nobre [35]

ICU

Severe sepsis & septic shock

79

PCT d1 > 1 μg/l :

- 39 PCT-guided arm

• Stop if PCT d5 decreased by > 90% or PCT < 0.25 μg/L

- 40 control arm

PCT d1 < 1μg/l :

• Stop if PCT d3 < 0.1 μg/l (but not before d5 if bacteremia)

Hochreiter [70]

ICU

Sepsis

110

Stop if clinical symptoms resolved and PCT < 1 μg/L (or dropped by 25% - 35% over 3 days if initial PCT > 1 μg/L)

(Infection + 2 SIRS criteria)

- 57 PCT-guided arm

- 53 control arm

Schroeder [73]

ICU

Severe sepsis after abdominal surgery

27

Stop if clinical symptoms resolved and PCT < 1 μg/L (or dropped by 25% - 35% over 3 days if initial PCT > 1 μg/L)

- 14 PCT-guided arm

- 13 control arm

Stolz [69], ProVAP trial

ICU

VAP

101

Daily PCT measurements PCT from d3 on

- 51 PCT-guided arm

Stop when PCT < 0.5 μg/L or dropped by ≥ 80% from initial value but stopping discouraged if PCT >1 μg/L

- 50 control arm

Bouadma [33], PRORATA trial

ICU

Sepsis, severe sepsis

621

Daily PCT measurements from d3 on

- 307 PCT-guided arm

Stop when PCT < 0.5 μg/L or dropped by ≥ 80% from initial value

- 314 control arm

CAP community-acquired pneumonia, ICU intensive care unit, PCT procalcitonin, RTI respiratory tract infection, SIRS systemic inflammatory response syndrome, VAP ventilator-associated pneumonia.

In outpatients and emergency room patients (excluding ICU patients), a serum PCT level below 0.25 ng/mL obtained 3 days or more after initiation of antibiotics, or a more than 80% decrease from the peak PCT level, allows stopping therapy.

Five studies have enrolled ICU patients with community- or hospital-acquired infection; four used a similar algorithm and the fifth used a different algorithm. It seems reasonable to recommend using the algorithm tested on the largest number of patients, i.e., as in the ProVAP et Prorata studies [33, 69], where stopping therapy was strongly encouraged when the serum PCT level was <0.5 ng/mL at 3 days or more after initiating antibiotics, or an >80% decrease from the maximal serum PCT value was recorded.

Does the site of infection (known, presumed, unknown) influence the utility of biomarkers to help withdrawing antibiotics?

In all studies examining the prognostic and follow-up value of PCT, the site of infection was known, to the exception of a few patients (n = 18) in the PRORATA study (10 and 8 in the PCT arm and control group, respectively). This small number does not allow any conclusion for this subgroup. It should be noted that patients having infective endocarditis, bone and joint infection, acute mediastinitis, intracerebral or intra-abdominal abscess were excluded from the above studies. Therefore, PCT-based algorithms cannot be used in these patients for discontinuing antibiotics.

Therefore, PCT-guided interruption of therapy can be used as indicated above in patients having a clinically documented site of infection to the exception of those sites listed above, which were excluded from clinical trials. When the site of infection is unknown, insufficient data are available to make a recommendation.

Does microbiological documentation influences the clinical utility of biomarkers to help withdrawing antibiotics?

Microbiologically documented infection

In the PRORATA study, most patients enrolled (70%) had microbiologically documented infection (222 and 213 in the PCT and control group, respectively) [33]. In the subgroup of 108 patients having positive blood cultures (55 and 53 in the PCT and control group, respectively), those randomised to the PCT-guided algorithm received 3 days less antibiotics than those enrolled in the control group (IC95%, -6 to 0.1 day, p = 0.06), without difference in mortality rate.

In the ProHosp trial, 72 patients had positive blood cultures [25]; patients enrolled in the PCT-guided therapy group received 5 days less antibiotics (10.3 vs. 15.1 days). Among 237 patients with bacteremic LRTI included in a recent meta-analysis [32], those treated with the aid of a PCT-based algorithm had 3.5 less antibiotic days (95% CI 1.55-5.54, p < 0.001), without significant difference in mortality rate (OR 1.09; 95% CI 0.51-2.31).

Lack of microbiological documentation

Most studies conducted outside of the ICU have enrolled patients in whom microbiological documentation was lacking. Although this specific subgroup has not been examined separately in individual studies or meta-analyses, it seems reasonable to recommend using a PCT algorithm in the non-ICU population to help decide stopping antibiotic therapy.

Most ICU patients enrolled in the above mentioned studies had documented infection. However, in the PRORATA study [33], 186 episodes were nondocumented and those treated in the PCT-guided therapy arm had a nonsignificant reduction in antibiotic days (2.4 less days), with no difference in mortality rate. Therefore, the documentation of infection does not appear to influence the impact of PCT-guided withdrawal of therapy, whether in ICU or non-ICU populations.

Does an immunocompromised status of patients influence the use of biomarkers for stopping antibiotic therapy?

Among the nine trials testing the impact of PCT-guided discontinuation of therapy, only the PRORATA trial [33] enrolled immunocompromised patients in the ICU. This trial enrolled patients having HIV infection or AIDS, organ transplant recipients, patients having haematological malignancy or receiving chemotherapy or radiation therapy, immunosuppressive agents or long-term steroids, to the notable exception of bone marrow transplant recipients or those having severe neutropenia (<500 leucocytes/mm3). About a hundred such immunocompromised patients were included (47 and 51 in the PCT-guided therapy group and control group, respectively). In this subgroup, PCT-guided discontinuation of therapy was associated with a significantly reduced duration of therapy (3.6 days; 95% CI, 0.2-7 days), without apparent effect on morbidity or mortality (control vs. PCT, -7.1%; 95% CI -18.7 to 4.5%).

Therefore, PCT-guided algorithms to reduce the duration of antibiotic therapy can be used safely in immunocompromised patients, to the exception of neutropenic patients (<500 neutrophils/mm3) or bone marrow transplant recipients, which were excluded from trials and in whom PCT-guided therapy cannot be recommended.

Does the impact of PCT-guided therapy vary according to the severity of acute illness?

Systematic reviews and meta-analyses

Six studies were reviewed in the meta-analysis by Tang et al. [74], totalling 1,548 patients. Four of these trials enrolled patients with suspected LRTI, two studies enrolled patients with sepsis, and one focused on severe infections in surgical ICU patients. Algorithms used varied across studies, using 2, 3, or 4 PCT levels for decision-making. There was a nonsignificant trend to a reduced duration of antibiotic therapy among LRTI studies (p = 0.067), which showed significant heterogeneity between trials. Conversely, in the other three studies of sepsis and surgical patients that enrolled more severe patients, no substantial heterogeneity was observed, and PCT-based algorithm for discontinuation of antibiotics were associated with a significant reduction in antibiotic duration, without apparent deleterious effect. This meta-analysis did not, however, stratify trials according to the severity of illness. In the subgroup of four studies having the strongest design (including 3 of the 4 studies on LRTI), there was a significant reduction in the duration of antibiotic therapy, but a significant heterogeneity persisted.

Significant heterogeneity also was evidenced in a recent meta-analysis including eight studies of LRTI [75]. There was one trial in patients with acute exacerbation of COPD, one on patients with CAP, two on patients with upper and lower RTI [16], and three on LRTI. A significant reduction of antibiotic duration was noted in all but one study [16], where a PCT-based algorithm was not used. Similarly to the previous analysis, this meta-analysis did not stratify patients according to their severity.

In the more recent systematic review by Schuetz et al. focusing on LRTI [32], 14 trials totalling 4,221 patients were analysed. A reduced rate of treatment initiation was confirmed in studies performed in primary care and patients having upper or lower RTI or acute bronchitis. Trials performed in the emergency department or the ICU and enrolling patients with LRTI, whether CAP or VAP, also found a reduction in the duration of antibiotic therapy. A sensitivity analysis showed no significant difference in the reduction of antibiotic duration according to the type of LRTI and site of care. It was however noted that the observance of clinical algorithms was lower in the ICU setting than at other sites.

Individual studies

Christ-Crain et al. [18] reported that PCT levels increased with the severity of illness, as assessed by the pneumonia severity index (PSI). However, the duration of antibiotic prescription decreased similarly with PCT-guided therapy in the low-risk (PSI I-III) or high-risk (PSI IV-V) group. In another study in patients with LRTI from the same group [17], only admission PCT levels were recorded but not duration of therapy. In the PROHOSP study [25], the reduction of antibiotic duration with PCT-guided therapy was more marked among patients having acute bronchitis (-65%) than among patients with acute exacerbation of COPD (-50%), and lowest (-32%), but still strongly significant, among those with CAP.

In the trial conducted by Stolz et al. in patients with acute exacerbation of COPD [20], the impact of PCT-guided therapy was not analysed according to the severity of the episode or of the underlying COPD, which included all severity stages.

Briel et al. enrolled patients with RTI from various causes, including upper respiratory tract infection or acute bronchitis, CAP, or acute exacerbation of COPD [15]. The reduction in antibiotic duration was more marked in the former group than in those with CAP or acute exacerbation of COPD.

The proREAL trial also enrolled patients (n = 1,759) with acute bronchitis, exacerbation of COPD, and CAP [27]. The observance of the algorithm was 81%, 70%, and 64% respectively, confirming other observations [32, 33] that the observance decreases with increasing severity of illness. Of note, the algorithm used in that study included both the clinical context and PCT levels (Table 3).

Long et al. also found a reduction in antibiotic duration of patients with CAP [22]. However, this study enrolled only patients with nonsevere pneumonia and cannot inform this assessment according to severity of illness. In trials dealing with the more severe infections (VAP, sepsis) [33, 35, 65, 66], analyses have not been stratified according to the level of severity.

Summary and conclusions

In view of currently available data, PCT is the only biomarker that has been extensively studied so far to help decision-making in discontinuing antibiotic therapy in adults. In clinical practice, an algorithm should be used, based on PCT levels on day 1 (reference value), then at day 2–3, and every 48 h until antibiotic therapy is stopped.

In nonimmunocompromised patients treated for RTI as outpatients or hospitalised in regular wards, the following stopping rule can be used: discontinuation of antibiotic therapy if the PCT level at day 3 is lower than 0.25 ng/mL or has decreased by >80-90% relative to the maximal value initially recorded, whether or not microbiological documentation has been obtained.

For patients hospitalised in ICU, including immunocompromised patients (but not neutropenic patients or bone marrow transplant recipients), the following decision rule can be suggested for nonbacteremic patients with a known site of infection (whether or not microbiological documentation is obtained): stopping antibiotics if the PCT level at day 3 is <0.5 ng/ml or has decreased by >80% relative to the highest level recorded during this episode. In bacteremic patients, a minimal duration of therapy of 5 days is recommended.

Overall, the severity of the infectious episode does not appear to alter substantially the impact of PCT measurements on the reduction of antibiotic duration; however, the magnitude of the reduction is more marked in infections of lesser severity, which likely reflects at least two factors: 1) the less common indications for antibiotic therapy in such conditions, which is in contrast to the high tendency among physicians to initiate therapy when in doubt on the aetiology; 2) the better observance of decision algorithms by physicians, likely related to their greater confidence in the lack of serious risk associated with withholding or withdrawing antibiotics in these low-severity patients.

Abbreviations

AIDS: 

Acquired immunodeficiency syndrome

AUC: 

Area under the curve

AUROC: 

Area under the receiver operating curve

BM: 

Bacterial meningitis

BMS: 

Bacterial meningitis score

CAP: 

Community-acquired pneumonia

COPD: 

Chronic obstructive pulmonary disease

CRP: 

C-Reactive protein

CSF: 

Cerebrospinal fluid

HIV: 

Human immunodeficiency virus

ICU: 

Intensive care unit

IFN-Υ: 

Interferon-gamma

IL: 

Interleukin

LRTI: 

Lower respiratory tract infection

PCT: 

Procalcitonin

PMN: 

Polymorphonuclear neutrophil

PPV: 

Positive predictive value

PSI: 

Pneumonia severity index

ROC: 

Receiver Operating Characteristic curve

RTI: 

Respiratory tract infection

SIRS: 

systemic inflammatory response syndrome

sTREM-1: 

soluble Triggering Receptor Expressed on Myeloid cells-1

TNF: 

Tumor necrosis factor

VAP: 

ventilator-associated pneumonia.

Declarations

Acknowledgment

The Expert Panel work was conducted under the auspices of the Maurice Rapin Institute.

Authors’ Affiliations

(1)
Service de réanimation médicale, CHU Dijon & Université de Bourgogne
(2)
Centre d’investigation clinique, INSERM CIE 1
(3)
Service de Réanimation Médicale, Institut de Cardiologie, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Université Pierre et Marie Curie - Paris VI
(4)
Service de Pneumologie et Soins Intensifs Respiratoires, Hôpitaux Universitaires Paris Centre, AP-HP & Université Paris-Descartes
(5)
Service de Pédiatrie Générale, CHU Necker-Enfants Malades, AP-HP, Université Paris Descartes
(6)
Inserm U953
(7)
Laboratoire Interactions Muqueuses Agents Pathogènes, EA562, UFR Médecine, Université de Bourgogne
(8)
Département d’Urgences Médicales, Centre Hospitalier Princesse Grace
(9)
Pôle d'Anesthésie Réanimation, CHU d’Angers
(10)
Service de réanimation, Centre hospitalier de Versailles
(11)
Laboratoire de Microbiologie, Institut Mutualiste Montsouris
(12)
Service de réanimation polyvalente, Groupe hospitalier Paris Saint Joseph
(13)
Pôle d'Anesthésie-Réanimation, Hôpital de Rangueil, CHU de Toulouse
(14)
Clinique Médicale et Service d'Urgences Pédiatriques, Hôpital Mère-Enfant, CHU Nantes
(15)
Département de Biochimie, Hopital Lapeyronie, CHU Montpellier
(16)
Intensive Care - SIRS Unit, University Hospitals of Geneva
(17)
Service de maladies infectieuses et tropicales, Université 1 de Grenoble, CHU de Grenoble
(18)
Centre de Recherche Clinique, Groupe hospitalier Paris Saint Joseph, Université Paris Descartes
(19)
Unité de réanimation, CHU Hôtel Dieu, AP-HP
(20)
Service de Réanimation médicale, Hôpitaux Universitaires Henri Mondor, AP-HP & Université Paris-Est
(21)
Inserm U957, Institut Pasteur

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