Monday, October 1, 2012

Are There Pros to Procalcitonin?

The Gist:  Procalcitonin (PCT) is gaining popularity in identification of serious bacterial infections and in attempts to curtail antibiotic usage; however, it has many limitations and has not been proven to conclusively and consistently alter patient oriented outcomes.  An elevated PCT may indicate infection, but this goes out the window in trauma or surgery.  The data seem to support using PCT over other biomarkers to help inform length of antibiotic use, especially in respiratory infections (i.e. if it falls to <0.5 mcg/L then it's likely safe to cease antibiotics) but any patient benefit derived from this is unclear.  This benefit is derived after the decision to initiate antibiotics has been made.  

As part of my clerkship, I recently attended a lecture on the use of PCT in the ED and ICU for sepsis identification and management.  The lecture was overwhelmingly promising - a better biomarker to aid in an attempt to sort out bacterial infections and stratify sick from less-sick patients in clinically murky situation?  Sounds awesome, but the lecture was industry sponsored and FOAM has taught me to ask a few questions about any diagnostic method I employ.  What does the test actually indicate (if positive or negative)?  How good is it, really?  How will it change my management of this patient?  Is it costly?  Timely?  Thus, I decided to investigate the test for myself.  Naturally, I went to my trusty FOAM sources to aid in this endeavor.
  • I started with PulmCCM.org, where I recalled reading several things on procalcitonin.  They have an fantastic review on use of procalcitonin and pneumonia, which also answers some of the more general questions about procalcitonin.  They also have a summary of some recent literature reviews
  • Then however, it was time to go to the pool, so I found a free talk by Dr. Talan on procalcitonin in the ED.  
  • In typical FOAM fashion, two days later, a brand new podcast on PCT (episode 194) by the Society of Critical Care Medicine started playing while I was at the gym.  It's a good review of some recent literature and some projections for the future of PCT.
Basics of Procalcitonin
  • More specific for bacterial etiology compared with other markers such as WBC and c-reactive protein (CRP) due to interferon-gamma from host response to virus (1)
  • Short half-life so theoretically easily trended and reflects patient's current situation (1)
  • Not as altered by inflammatory states, glucocorticoids, or other known drugs as WBC and CRP; however, it does rise immediately after major trauma and surgery in the absence of bacterial pathogens (1)
  • Costs ~$25 per test in the US (charge is ~$38)
Below is essentially a run-down of the primary sources referenced in the above reviews (it's covered by the FOAM sources above, but I'm trying to get better at going through the primary literature).  Note:  most of these studies looked at PCT use in patients with respiratory symptoms, many studies are funded by the manufacturer, and some of them use various cut-off points for interventions.  I've also left off some of the old studies that used the older assay not currently widely used in the U.S.

Identification of Serious Bacterial Infections (SBI) - not ready for prime time.
  • Sudhir et al found that PCT was "positive" (>0.5mcg/L) in 94% of their 100 patient septic cohort (older assay)
  • 2010 pediatric study randomized febrile kids to either have a PCT value available to the provider or not.  Used a cut off of 0.5 mcg/dL.  Sensitivity of PCT for SBI 77%, Specificity 64%
  • June 2011 study by Bafadhel et al evaluated PCT and CRP values in Community Acquired Pneumonia (CAP) versus COPD/asthma.  For identifying pneumonia, CRP >48 mg/L had a sensitivity of   91% (95% CI, 80%-97%), specificity 93% .  A PCT of 0.8 mcg/L had a sensitivity of 89% (95% CI, 78%-95%) and specificity of 78% (95% CI, 72%-82%). 
  • Meynaar et al evalued PCT in 76 patients (cut offs of 2 mcg/L and 10 mcg/L) and have a nice table of the Se, Sp, and OR compared with other biomarkers
  • This study by El-Solh et al in Critical Care Medicine 2011 did not differentiate between aspiration pneumonitis and bacterial aspiration pneumonia.
  • Muller et al published an analysis of the ProHosp data and found that patients with PCT levels <0.25 mcg/L were extremely unlikely to have positive blood cultures (<1%) 
  • Reynolds et al found that shock elevates PCT levels regardless of bacterial infection in a study of medical ill and post-operative patients.  Higher PCT levels were assosciated with infection, but this data support the notion that general inflammation does affect PCT levels regardless of the presence of bacterial pathogens. 
Clinically meaningful outcomes for patients
Morbidity/Mortality - probably no difference in mortality using PCT guided algorithms, questionable change in length of stay
  • In the ProHOSP RCT by Schuetz et al in 2009, utilization of PCT did not reduce the incidence of adverse effects (primary outcome of the study), although the authors conclude that the incidence was "similar." 
  • Another 2011 systematic review by Schuetz et al (who published many of the PCT trials) showed no mortality difference in patients with PCT guided therapy versus standard care groups despite reduced antibiotic usage in the PCT guided cohort
Length of Stay (LOS) - unlikely that PCT has any effect. Would you discharge someone based solely on a lab value?  I'm pretty sure everyone uses the clinical picture in this setting.
  • In Agarwal and Schwartz's systematic review, only 2 studies demonstrated decreased LOS.
  • Jensen et al's 2011 study in Critical Care Medicine investigate the effect of using an algorithm based on PCT values to escalate antimicrobial therapy (escalated at 1 mcg/L, a higher cut-off level than the 0.5 mcg/L used in most other studies).  The study, reviewed here by EM Lit of Note, demonstrates that there's actually an increase antibiotic usage, LOS, and ventilator dependent days.  
Antibiotic Usage - studies pretty consistently demonstrate that trending  PCT can reduce the length of antibiotic usage in respiratory infections but should not be used to initiate antibiotics.
  • June 2011 study by Bafadhel et al  Derivation of PCT values to guide therapy: PCT value of > 0.25 ng/mL would have incredibly reduced antibiotic usage in patients with asthma or COPD exacerbations while slightly reducing the antibiotic usage in the pneumonia cohort.  Counterpoint:  A CRP value of >48 mg/L also resulted in very similar reductions
    • Asthma - from 57% to 4% (reduction in antibiotic usage of 93%; 95% CI, 88%-98%)
    • COPD - from 76% to 7% in patients with exacerbation of COPD (reduction of 91%; 95% CI, 87%-95%)
    • Pneumonia - from 100% to 73% (reduction of 27%; 95% CI 17%-40%).
  • Antibiotic duration in PCT group 5.7 days vs 8.7 days in standard care group in the ProHosp trial 
  • A 2011 systematic review by Agarwal and Schwartz (including only RCTs) concluded that use of PCT to inform antibiotic length decreases usage of antimicrobials.
  • The primary outcome of the  2010 pediatric study was antibiotic usage, which was the same in the group who had PCT available and those that did not.  If antibiotics were given to all kids with a PCT >0.5 mcg/L, more antibiotics would have been utilized (24% 95% CI, 15-33), not less.  Additionally, there's an argument that an even lower cutoff value should be employed (0.25 mcg/L has been proposed)
  • Schuetz et al's systematic review  concluded that PCT reduced antibiotic duration and prescriptions in the outpatient, ED, and ICU settings for patients with respiratory infections (note: included more trials than the Agarwal and Schwartz trial). 
  • Not all studies demonstrating a statistically significant reduction in the exposure to antibiotics, including the 2009 Schuetz RCT, used this as a primary endpoint in the study.  In this cohort for lower respiratory tract infections, the mean length of antibiotic exposure was 5.7 days in the PCT group compared with 8.7 in the standard care group. 
  • Limiting initiation of antibiotic therapy is probably not effective at a cut-off of 0.5mcg/L (so use your clinical judgment) (2)
Risk Stratification 
  • EPs are good at determining who is extremely ill and those who aren't that sick but in situations where the patient can seem to go either way, lab tests may help. Harbarth et al found that patients on the SIRS/sepsis spectrum had poorer prognoses if their PCT levels didn't fall (3).
    •  High risk:  PCT levels >2 mcg/L.  
    • Low risk: < 0.25 mcg/L  
    • The cut-off of 0.5mcg/L seems to be the most referenced
Economics - the test is presently more expensive than the vague counterparts, the WBC count and CRP.  However, some argue that there are cost savings in LOS reduction, antibiotic usage, blood cultures (using PCT as a surrogate - see Muller et al Table 5), and reduced ICU days.  Presently, most of these arguments are projection of data based on derivation and internal, retrospective validation of certain PCT cut off and theoretical algorithms.  

PCT is gaining steam in the US.  The test llooks better than WBC and CRP so far, but studies are beginning to show that the test has some confounding issues.  Exercise caution when ordering PCT and recognize the soft lines drawn for the "cut-off" levels of the test.

References:
1.  Jin M et al Procalcitonin: Uses in the Clinical Laboratory for the Diagnosis of Sepsis Lab Medicine 2010 41, 173-177 
2.  Agarwal and Schwartz.  Procalcitonin to Guide Duration of Antimicrobial Therapy in Intensive Care Units: A Systematic Review Clin Infect Dis.53 (4):379-387.
3. Harbarth et al.  Diagnostic Value of Procalcitonin, Interleukin-6, and Interleukin-8 in Critically Ill Patients Admitted with Suspected Sepsis Am. J. Respir. Crit. Care Med.vol. 164no. 3 396-402

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