Adding PCT results to clinical assessment improves the accuracy of the early clinical diagnosis of sepsis. • PCT levels accurately differentiate sepsis from noninfectious inflammation*[r]
(1)Update on Sepsis Biomarkers
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
(2)Community Acquired Pneumonia (CAP)
♦ 5.16-6.11 cases/1000 persons/year
• > 900,000 episodes/yr occur in adults > 65 yrs of age
• ~20% require hospitalization
♦ > 60,000 deaths in United States in 2005
• 8th most common cause of death
♦ 30-day mortality for hospitalized pts with CAP: 23%
(3)Community Acquired Pneumonia
♦ Estimated annual direct medical costs of care: $8.5 billion
♦ 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
♦ ↑’ed LOS, risk of adverse events, and emergence of resistance are
negative outcomes associated with unnecessary Abx
(4)Interventions to Reduce Abx Exposure
♦ Short-course therapy for CAP: clinically as effective as
long-course therapy and associated with fewer adverse events
♦ IV to PO conversion: safe at 48-72 hr, even in pts with severe
CAP, who meet criteria for clinical stability
♦ Biomarkers: use to guide the need for Abx at the start of and
during therapy leads to reduced Abx exposure without evidence of pt harm
(5)(6)6
6
Objectives
♦ Describe pathophysiology of Procalcitonin (PCT)
♦ Describe use of PCT in diagnosis and prognosis of severe sepsis and septic shock
(7)7
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
(8)8
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
(9)9
Biomarkers in Sepsis Diagnosis
Sepsis is currently diagnosed using clinical definitions combined with
(10)Blander & Sander Beyond pattern recognition: five immune checkpoints for scaling the microbial threat Nature Reviews Immunology12, 215-225 (March 2012)
Pathogen-Associated Molecular Patterns
(11)Procalcitonin (PCT)
♦ 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
• levels return to normal within a few hrs
• high variability of markers: major challenge for clinical utility
♦ C-reactive protein (CRP): ↑’es slowly with peak ~ 48-72 hr
• considered biomarker for inflammation, rather than infection
(12)Procalcitonin
♦ 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
(13)Time course PCT successful treatment 13 10 12 14 16 18 20
1
PCT Level
PCT Level
(14)14
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
(15)15
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
Sensitivity: 94% Specificity: 77%
(16)PCT Regulation on Cellular Level
♦ Induced in response to microbial toxins and bacterial-induced
cytokines (IL-1, IL-6, and TNF-α)
• released into bloodstream where it can be measured
♦ Conversely, production attenuated by cytokines released in
response to viral infection (interferon (INF)-γ)
(17)17
17
♦ 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
(18)Useful Diagnostic Biomarker
♦ 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
(19)Utility in Clinical Settings
♦ 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 hr
before SIRS induced by injection of E coli lipopolysaccharide (LPS)
• PCT: no inhibition within study period
• Other biomarkers: significantly inhibited in dose-dependant way
♦ PCT production does not rely on WBCs
• Dynamics are expected to be comparable in neutropenic pts
(20)Commercial Detection Assays
♦ 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 µg/mL
• Based on sheep polyclonal anticalcitonin Ab
• Assay used in most intervention studies
♦ VIDAS system from bioMerieux: equally sensitive assay
(21)Diagnosis & Prognosis
♦ 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
(22)Diagnosis Dilemma
♦ 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
• For example, self-limiting viral LRTIs will also recover despite Abx therapy
♦ In sepsis and pneumonia, performance of PCT as a tool for Abx
guidance is best measured in randomized intervention trials
• Assuming there was no outcome-relevant bacterial infection if the pt recovers without Abx therapy
(23)PCT Cutoff Ranges
♦ 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
(24)PCT Algorithm in LRTIs
♦ 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
• Namely in life-threatening disease or immediate need for ICU
admission because of respiratory or hemodynamic instability
(25)(26)ProRESP Trial
♦ 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
(27)ProCAP and ProCOLD
♦ 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
♦ ProCAP: 302 pts with mostly severe CAP (>60% with PSI IV & V) • PCT-guided therapy: Abx courses 65% shorter than in standard regimens
♦ ProCOLD: 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
• Safety and Outcomes: Re-exacerbation rates and FEV-1 improvement over
6-mo were same in intervention and control groups
(28)♦ Large multicenter trial
– 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
(29)Additional a priori 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
(30)Additional a priori 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%
(31)♦ In 2012, all these data were pooled in large meta-analysis
using individual data of 4221 patients in 14 trials
♦ Markedly reduced Abx exposure overall
• 8d vs 4d and adjusted difference of -3.47d (95% CI: -3.78 to -3.17)
• No increase in mortality or treatment failure
(32)Meta-analysis Results
♦ Primary care setting: mainly due to ↓ Rx rates (23% vs 63%) • Pts with upper ARI: 15% vs 48%, adjusted OR: 0.14 [95% CI: 0.09-0.22]
• Pts with bronchitis: 24% vs 66%, adjusted OR: 0.15 [95% CI: 0.10-0.23]
♦ In ED and ICU pts, shorter courses of Abx treatment were found
• ED: 7d vs 10d, difference - 3.7d [95% CI: - 4.09 to - 3.31]
• ICU: 8d vs 12d, difference - 3.17d [95% CI: - 4.28 to – 2.06]
♦ In CAP, Abx exposure markedly shorter:
• Difference – 3.34d [95% CI: - 3.79 to – 2.88]
• Associated with lower risk of treatment failure (19.1% vs 21.9% in standard treatment arm) adjusted OR: 0.82; 95% CI: 0.71 – 0.97
(33)Results: All Subjects
(34)Results: Exacerbated COPD
(35)Assay Characteristics
♦ 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
• Results readily available around the clock and within hr
(36)Implications for Antimicrobial Stewardship
♦ 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
• Results frequently inadequately implemented in daily practice
♦ Aujesky et al: 37.4% of pts with low PSI scores hospitalized
• Mainly due to comorbidities
• Reflects difficulty of implementing guidelines into clinical practice
(37)PCT Registry Study
♦ 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)
♦ 73% of pts treated according to PCT-guided algorithm
• Abx therapy applied in 71% of pts
• Median duration of treatment: 6d
• Significant improvement when compared to control group from previous trial at same hospital (ProHOSP)
(38)ProREAL
♦ 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
• 5.9d vs 7.4d; difference – 1.51d [95% CI: - 2.04 to – 0.98]
♦ No increase in risk of combined adverse outcome end point within
30d of follow-up in respect to withholding Abx and early cessation
(39)Associations of Procalcitonin Testing with Clinical Outcomes and Antibiotic Use
Procalcitonin Group (n = 3336)
Control Group (n = 3372) Between-Group Difference (95%
CI) Adjusted OR (95% CI)a
P Value
Clinical Outcomes
30-d mortality, No (%) 286 (8.6) 336 (10.0) 0.83 (0.70 to 0.99) .04
Treatment failure, No (%)b 768 (23.0) 841 (24.9) 0.90 (0.80 to 1.01) .07
Length of ICU stay, median (IQR), d 8.0 (4.0 to 17.0) 8.0 (4.0 to 17.0) 0.39 (−0.81 to 1.58) .52
Length of hospital stay, median (IQR), d 8.0 (2.0 to 17.0) 8.0 (2.0 to 17.0) −0.19 (−0.96 to 0.58) .63
Antibiotic-related adverse effects, No./total (%) 247/1513 (16.3) 336/1521 (22.1) 0.68 (0.57 to 0.82) .001
Antibiotic Exposure
Rates for initiation of antibiotics, No./total (%) 2351/3288 (71.5) 2894/3353 (86.3) 0.27 (0.24 to 0.32) .001
Duration of antibiotics, median (IQR), d 6.0 (4.0 to 10.0) 8.0 (6.0 to 12.0) −1.83 (−2.15 to −1.50) .001
(40)Procalcitonin Conclusions
♦ 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
(41)Conclusions
♦ Short-course therapy for CAP: clinically as effective as long-course therapy and associated with fewer adverse events
♦ IV to PO conversion: safe at 48-72 hr, even in pts with severe CAP, who meet criteria for clinical stability
♦ Procalcitonin: use to guide the need for Abx at the start of therapy leads to reduced Abx exposure without
(42)(43) Blander & Sander