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<b>Update on Sepsis Biomarkers </b>

William T. McGee, M.D. MHA, FCCM, FCCP
Critical Care Medicine

Associate Professor of Medicine and Surgery
University of Massachusetts

759 Chestnut Street, Springfield, MA 01199
Tel: 413-794-5439 | Fax: 413-794-3987

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<b>Community Acquired Pneumonia (CAP)</b>

♦ _{5.16-6.11 cases/1000 persons/year}

• <i><b>> 900,000 </b>episodes/yr occur in adults > 65 yrs of age</i>

• <i><b>~20% </b>require hospitalization</i>

♦ <b>_{> 60,000}</b>_{deaths in United States in 2005}

• <i>8th</i> <i>_{most common cause of death}</i>

♦ _{30-day mortality for hospitalized pts with CAP:}<i><b>_23%</b></i>

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<b>Community Acquired Pneumonia</b>

♦ _{Estimated annual direct medical costs of care:}<b>_{$8.5 billion}</b>

♦ _{Given magnitude of antibiotic (Abx) use associated with CAP,}

ensuring correct diagnosis and appropriate empiric as well as
definitive therapy for optimal course to achieve clinical cure and
reduce risk of ADEs is critical

♦ _{Adherence to Abx guidelines improves survival in pts with CAP}

• adherence to Abx treatment guidelines is inconsistent and the
erroneous diagnosis of CAP and misuse of Abx is prevalent

♦ <b>_↑’</b>_{ed LOS, risk of adverse events, and emergence of resistance are}

negative outcomes associated with unnecessary Abx

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<b>Interventions to Reduce Abx Exposure</b>

♦ <b>_{Short-course therapy for CAP}</b>_{: clinically as effective as}

long-course therapy and associated with fewer adverse events

♦ <b>_{IV to PO conversion}</b>_{: safe at 48-72 hr, even in pts with severe}

CAP, who meet criteria for clinical stability

♦ <b>_Biomarkers</b>_{: use to guide the need for Abx at the start of and}

during therapy leads to reduced Abx exposure without
evidence of pt harm

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<b>6</b>

<b>6</b>

Objectives

♦ Describe pathophysiology of Procalcitonin (PCT)

♦ Describe use of PCT in diagnosis and prognosis of
severe sepsis and septic shock

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<b>7</b>

Biomarkers

♦ Characteristic that is objectively measured and

evaluated as an indicator of normal biological process,
pathogenic process, or pharmacologic response to a
therapeutic intervention

♦ Usefulness is evaluated by:

– Capacity to provide timely information beyond what is readily
available from routine physiologic and clinical data (Speed +
Accuracy)

– Sensitivity and specificity

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<b>8</b>

Potential Role(s) for Biomarkers

♦ Identify patient with ↑ probability of disease, adverse

outcome, or benefit from intervention

♦ Identify presence or absence of pathologic state or
process

♦ Aid in risk stratification/prognosis

♦ Monitor response to an intervention or treatment

♦ Serve as surrogate endpoint

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<b>9</b>

Biomarkers in Sepsis Diagnosis

Sepsis is currently diagnosed using
clinical definitions combined with

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Blander & Sander. <b>Beyond pattern recognition: five immune checkpoints for </b>
<b>scaling the microbial threat. </b><i>Nature Reviews Immunology</i><b>12</b>, 215-225 (March 2012)

<b>Pathogen-Associated Molecular Patterns </b>

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<b>Procalcitonin (PCT)</b>

♦ _{Precursor peptide of mature hormone calcitonin}

♦ _{Released in multiple tissues in response to bacterial infections via}

direct stimulation of cytokines

♦ _{Cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)}

show fast initial spike upon infection

• <i>levels return to normal within a few hrs</i>

• <i>high variability of markers: major challenge for clinical utility</i>

♦ _{C-reactive protein (CRP): ↑’es slowly with peak ~ 48-72 hr}

• considered biomarker for inflammation, rather than infection

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<b>Procalcitonin</b>

♦ _{Increases promptly within 4-6 hrs upon stimulation and ↓’es}

by ~ 50% daily if bacterial infection is controlled by immune
system and supported by effective Abx

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Time course PCT successful treatment

<b>13</b>
0
2
4
6
8

10
12
14
16
18
20

1 2 3 4 5 6 7 8

<b>PCT Level</b>

PCT Level

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<b>14</b>

Simon L. et al. Clin Infect Dis. 2004; 39:206-217.

Adding PCT results to clinical assessment improves the accuracy of the
early clinical diagnosis of sepsis

• PCT levels accurately differentiate sepsis from noninfectious inflammation*

• PCT has been demonstrated to be the best marker for differentiating patients with sepsis from
those with systemic inflammatory reaction not related to infectious cause

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<b>15</b>

Harbarth S et.al. AM J Resp Crit Care Med. 2001; 164:396-402

• When PCT is used as a reference, the sensitivity and specificity of sepsis

diagnosis can be significantly increased compared with conventional clinical
parameters.

<b>Sensitivity: 94%</b>
<b>Specificity: 77%</b>

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<b>PCT Regulation on Cellular Level</b>

♦ _{Induced in response to microbial toxins and bacterial-induced}

cytokines <i>(IL-1, IL-6, and TNF-α)</i>

• released into bloodstream where it can be measured

♦ _{Conversely, production attenuated by cytokines released in}

response to viral infection <i>(interferon (INF)-γ)</i>

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<b>17</b>

<b>17</b>

♦ How can we use this cellular signal of infection in the
management of both septic and non

septic patients

♦ Goals

– Provide antibiotic therapy to pts who need it as soon as possible

– Avoid antibiotic prescription to those without infection

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<b>Useful Diagnostic Biomarker</b>

♦ _{Helps distinguish bacterial infections from other inflammatory}

reactions or viral infections

♦ _{Strong correlation between concentration of PCT and extent}

and severity of bacterial infections has been observed in CAP

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<b>Utility in Clinical Settings</b>

♦ _{102 critically ill pts with systemic infections in ICU found similar PCT}

levels but lower CRP and IL-6 levels in pts treated with systemic
corticosteriods

♦ _{Study of 32 healthy volunteers treated with prednisolone 2 hr}

before SIRS induced by injection of <i>E. coli </i>lipopolysaccharide (LPS)

• <b>PCT</b>: no inhibition within study period

• <b>Other biomarkers</b>: significantly inhibited in dose-dependant way

♦ _{PCT production does not rely on WBCs}

• <i>Dynamics are expected to be comparable in neutropenic pts</i>

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<b>Commercial Detection Assays</b>

♦ _{Currently, different assays available for PCT with}

individual performance characteristics

♦ _{Reasonably low detection limit especially important}

when antimicrobial stewardship decisions intended

♦ _{Kryptor assay: lower level of detection of 0.06 àg/mL}

ã <i>Based on sheep polyclonal anticalcitonin Ab</i>

• <i>Assay used in most intervention studies</i>

♦ VIDAS system from bioMerieux: equally sensitive assay

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<b>Diagnosis & Prognosis</b>

♦ _{Inherent complexity evaluating diagnostic capability of a novel}

biomarker without presence of diagnostic reference standard

• Optimally, morphological verification such as growth of typical pathogens
or proving histopathology can be obtained to establish “correct” diagnosis

♦ _{Causative pathogen cannot be detected in 80% of pts with}

suspected bloodstream infections

♦ _{> 70% of pts with radiographically confirmed PNA}
• Causative microbe never identified/isolated

• Usually a syndromic definition of lower respiratory tract infections (LRTIs)

♦ _{No “gold standard” to discriminate bacterial from viral etiology}

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<b>Diagnosis Dilemma </b>

♦ _{Real-life concept focuses primarily on outcomes of pts with out}

without Abx therapy, while discarding alleged gold standards

♦ _{Potential dilemma: ambiguity in deciding whether a pt who}

received Abx “just to be sure” and subsequently recovers had a
good outcome because of OR despite Abx therapy

• <i>For example, self-limiting viral LRTIs will also recover despite Abx therapy</i>

♦ _{In sepsis and pneumonia, performance of PCT as a tool for Abx}

guidance is best measured in randomized intervention trials

• <i>Assuming there was no outcome-relevant bacterial infection if the pt </i>
<i>recovers without Abx therapy</i>

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<b>PCT Cutoff Ranges</b>

♦ _{Similar treatment recommendation algorithms based on PCT}

cutoff ranges were all used in all published stewardship studies

♦ _{4 classes of Abx treatment recommendations}

• Strongly discouraged

• Discouraged

• Recommended

• Strongly recommended

♦ _{Cutoff ranges derived from multilevel likelihood calculations}

obtained in observational studies

• Reflect likelihood of bacterial infection in a distinct entity of infection

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<b>PCT Algorithm in LRTIs</b>

♦ _{Initiation or continuation of Abx was more or less encouraged}

when levels > 0.5 µg/mL or > 0.25 µg/mL or discouraged when
levels were < 0.1 µg/mL or < 0.25 µg/mL

♦ When Abx therapy was withheld, clinical re-evaluation and a
2nd _{measurement of PCT performed after 6-24 hr if clinical}

condition did not improve spontaneously

♦ _{Specific “overruling” criteria were defined, were the algorithm}

could be bypassed and Abx initiated at physician’s discretion

• <i>Namely in life-threatening disease or immediate need for ICU </i>

<i>admission because of respiratory or hemodynamic instability</i>

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<b>ProRESP Trial</b>

♦ ₁st _{intervention study testing hypothesis that PCT can be used}

to guide initiation of Abx in pts with LRTI in the ED

♦ _{243 pts with LRTI}

• Outcomes of both groups were not different

• PCT-guided group: less Abx Rx (44 vs 83%)

• Strongest effect seen in pts with acute bronchitis and exacerbated COPD

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<b>ProCAP and ProCOLD</b>

♦ _{2 subsequent prospective RCTs evaluating effect of PCT}

guidance for Abx discontinuation in CAP and to assess pt safety
over 6-mo follow-up period in pts with exacerbated COPD

♦ <b>_ProCAP</b>_{: 302 pts with mostly severe CAP (>60% with PSI IV & V)}
• PCT-guided therapy: Abx courses 65% shorter than in standard regimens

♦ <b>_ProCOLD</b>_{: 208 pts with exacerbated moderate-to-severe COPD}
• PCT-guided therapy: Abx Rx’s reduced from 72% to 40% initially

• Lasting effect in follow-up period of 6-mo

• <i>Safety and Outcomes</i>: Re-exacerbation rates and FEV-1 improvement over

6-mo were same in intervention and control groups

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♦ _{Large multicenter trial}

– 6 hospitals in Switzerland with > 1300 pts

– Predefined web-based guidelines had to be followed for every pt in
control group in order to ensure optimal adherence to guidelines

♦ Abx exposure vs. treatment according to defined guidelines:

• ↓ by 32.4% in CAP; 50.4% in exacerbated COPD; 65% in acute bronchitis

♦ _{Overall reduction in Abx use translated into reduction in}

associated side effects of ~ 30% in pts treated according to PCT

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Additional

<i>a priori </i>

Results

• (B) Predictive value of baseline

PCT to determine + culture
(blood, urine, respiratory)

– Positive vs. Negative culture

• 9.8ng/mL [1.7-41.3] vs.
3.3ng/mL[0.6-15.8] p<0.001

• 61% of cultures were positive

• (C) Predictive value of baseline

PCT to determine sepsis
severity

– Septic shock vs. Sepsis

• 13.6ng/mL [2.7-55.2] vs. 3.6[0.5-15.6],
p<0.001

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Additional

<i>a priori </i>

Results

• Baseline PCT was similar in survivors and non-survivors however there was a
significantly faster decline overtime in the serial PCT levels in survivors

• Baseline cut off of ≤ 3ng/mL excluded positive blood culture with a sensitivity of
90% (95% CI, 82-89) and a NPV of 96% (95% CI, 93-99)

• Baseline cut off of ≤ 0.1ng/mL excluded positive culture in the first 72h with a
sensitivity of 100% and NPV of 100%

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♦ _{In 2012, all these data were pooled in large meta-analysis}

using individual data of <b>4221</b> patients in 14 trials

♦ _{Markedly reduced Abx exposure overall}

• <b>8d vs. 4d </b>and adjusted difference of <b>-3.47d </b><i>(95% CI: -3.78 to -3.17)</i>

• No increase in mortality or treatment failure

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<b>Meta-analysis Results</b>

♦ _{Primary care setting: mainly due to ↓ Rx rates} <b>_{(23% vs. 63%)}</b>
• Pts with upper ARI: <b>15% vs. 48%, </b>adjusted OR: 0.14 <i>[95% CI: 0.09-0.22]</i>

• Pts with bronchitis: <b>24% vs. 66%, </b>adjusted OR: 0.15 <i>[95% CI: 0.10-0.23]</i>

♦ _{In ED and ICU pts, shorter courses of Abx treatment were found}

• ED: <b>7d vs. 10d</b>, difference - 3.7d <i>[95% CI: - 4.09 to - 3.31]</i>

• ICU: <b>8d vs. 12d</b>, difference - 3.17d <i>[95% CI: - 4.28 to – 2.06]</i>

♦ _{In CAP, Abx exposure markedly shorter:}

• Difference <b>– 3.34d </b><i>[95% CI: - 3.79 to – 2.88]</i>

• Associated with lower risk of treatment failure (<b>19.1% vs. 21.9% </b>in
standard treatment arm) <i>adjusted OR: 0.82; 95% CI: 0.71 – 0.97</i>

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<b>Results: All Subjects</b>

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<b>Results: Exacerbated COPD</b>

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<b>Assay Characteristics</b>

♦ _{Timely decision making: great importance in bacterial}

infections

♦ _{2 retrospective studies: improved mortality in pts with}

CAP who received 1st _{dose of Abx within 4-8 hr}

♦ _{In all intervention trials, PCT measured using rapid}

sensitive assay with assay time of 20 min

• <i>Results readily available around the clock and within 1 hr</i>

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<b>Implications for Antimicrobial Stewardship</b>

♦ _{Key in real-life setting: strong adherence rate to PCT algorithm}

to have same effect of reduced Abx exposure in clinical
practice as found in controlled studies

♦ _{Unlike controlled studies were adherence is monitored}

• <i>Results frequently inadequately implemented in daily practice</i>

♦ <i>_{Aujesky et al}</i>_:<b>_37.4%</b>_{of pts with low PSI scores hospitalized}

• <i>Mainly due to comorbidities</i>

• <i>Reflects difficulty of implementing guidelines into clinical practice</i>

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<b>PCT Registry Study</b>

♦ _{Investigated feasibility/effectiveness of PCT-guided}

stewardship in real-life setting of medical clinic in Switzerland

♦ _{302 pts with LRTIs of all severities (64% PSI IV and V)}

♦ <b>_73%</b>_{of pts treated according to PCT-guided algorithm}

• Abx therapy applied in <b>71% </b>of pts

• Median duration of treatment: <b>6d</b>

• Significant improvement when compared to control group from
previous trial at same hospital (ProHOSP)

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<b>ProREAL</b>

♦ _{Study of 1759 pts in US, France, Switzerland}

♦ _{Overall adherence to PCT-guided stewardship in 68% pts}

• Adherence: acute bronchitis (81%); exacerbated COPD (70%); CAP (64%)

• Outpatient setting (86%) vs. Inpatient setting (66%)

♦ _{After multivariate adjustment, significantly shorter Abx}

exposure demonstrated with PCT algorithm

• <b>5.9d vs. 7.4d</b>; difference – 1.51d <i>[95% CI: - 2.04 to – 0.98]</i>

♦ <i>_{No increase in risk of combined adverse outcome end point within}</i>

<i>30d of follow-up in respect to withholding Abx and early cessation</i>

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<b>Associations of Procalcitonin Testing with </b>

<b>Clinical Outcomes and Antibiotic Use </b>

<b>Procalcitonin Group (n =</b>
<b>3336)</b>

<b>Control Group (n = 3372)</b> <b>Between-Group Difference (95%</b>

<b>CI)</b> <b>_{Adjusted OR (95% CI)}_a</b>

<b>P</b>
<b>Value</b>

<b>Clinical Outcomes</b>

<b>30-d mortality, No. (%)</b> 286 (8.6) 336 (10.0) 0.83 (0.70 to 0.99) <b>.04</b>

<b>Treatment failure, No. (%)b</b> 768 (23.0) 841 (24.9) 0.90 (0.80 to 1.01) <b>.07</b>

<b>Length of ICU stay, median (IQR), d</b> 8.0 (4.0 to 17.0) 8.0 (4.0 to 17.0) 0.39 (−0.81 to 1.58) <b>.52</b>

<b>Length of hospital stay, median (IQR), d</b> 8.0 (2.0 to 17.0) 8.0 (2.0 to 17.0) −0.19 (−0.96 to 0.58) <b>.63</b>

<b>Antibiotic-related adverse effects, No./total (%)</b> 247/1513 (16.3) 336/1521 (22.1) 0.68 (0.57 to 0.82) <b>.001</b>

<b>Antibiotic Exposure</b>

<b>Rates for initiation of antibiotics, No./total (%)</b> 2351/3288 (71.5) 2894/3353 (86.3) 0.27 (0.24 to 0.32) <b>.001</b>

<b>Duration of antibiotics, median (IQR), d</b> 6.0 (4.0 to 10.0) 8.0 (6.0 to 12.0) −1.83 (−2.15 to −1.50) <b>.001</b>

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<b>Procalcitonin Conclusions</b>

♦ _{Evidence supports PCT as accurate surrogate biomarker for}

likelihood and severity of bacterial infections

♦ _{In CAP and other respiratory infections, PCT-guided algorithms}

resulted in ↓’ed Abx exposure

• Maintaining similar or better level of safety compared with standard care

♦ _{Reductions in Abx use translate to decreased:}
• Costs, risk of side effects, and bacterial resistance

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<b>Conclusions</b>

♦ <b>Short-course therapy for CAP</b>: clinically as effective as
long-course therapy and associated with fewer adverse
events

♦ <b>IV to PO conversion</b>: safe at 48-72 hr, even in pts with
severe CAP, who meet criteria for clinical stability

♦ <b>Procalcitonin</b>: use to guide the need for Abx at the start
of therapy leads to reduced Abx exposure without

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