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Procalcitonin; What is the Clinical Value of this Biomarker in determining infection? Jonathan Shupe, MD Faculty CDA Family Medicine Residency Joseph Behunin, MD 3rd-year FM resident
Goals and Objectives • Better understand how PCT can help reduce Abx exposure in LRTIs • Consider algorithm based PCT approach to Abx use in LRTIs • Review PCT use in sepsis and ICU patients • Explore other conditions where PCT may be helpful • Consider limitations of PCT
73yo M with HTN and BPH presents to the ED with cough, fever, SOB • Temp: 37.2 • 94, 118/76, 26, O2 sat 86% on RA -> 98% on 2LNC • WBC 16, Lactate 1.4 • CXR: Lingular opacity consistent with infectious process • Ceftriaxone and azithromycin IV in the ED • CURB-65 and severity lead to patient being admitted to the general medical floor
Management • Diagnosis is community acquired pneumonia • Respiratory and blood cultures negative • Influenza negative • WBC normalizes • IV Abx converted to PO (3rd generation cephalosporin + completed 1500mg azithromycin) • Discharge patient home after 72 hours, normal vitals • But wait!!!, How many days do you continue the antibiotics?
How long to continue Abx? (sepsis, PNA) • 3 days because PNA can’t be that different than uncomplicated cystitis • 7-14 days because everything in medicine revolves around the Gregorian calendar • IDSA says treat for minimum of 5 days, longer if any clinical symptoms are still present • Consider following procalcitonin to determine when antibiotics can be stopped • Didn’t they say Stella opens up at 9am
Limitations of the Gold standard • Respiratory culture only positive and helpful 10% of the time • Sepsis etiology only determined 30-60% of the time • Cultures can be due to colonization • Biomarkers (CRP, IL-6) confer suboptimal sensitivity and specificity
Antibiotic stewardship • Most frequent indication for Abx prescriptions in North America is LRTIs • Up to 30-50% of abx given to hospitalized patients may be unnecessary (Fridkin et al. MMWR Morb Mortal Wkly Rep 2014) • Bacterial resistance • High cost • Adverse drug reactions
73yo M with HTN and BPH presents to the ED with cough, fever, SOB • Temp: 37.2 • 94, 118/76, 26, O2 sat 86% on RA -> 98% on 2LNC • WBC 16, Lactate 1.4 • CXR: LLL opacity, atelectasis and cannot rule out consolidation • Diagnosis? • Treatment?
What do you do next? • Continue Abx regimen, CXR likely negative due to dehydration • Check urinary legionella antigen • Use a procalcitonin algorithm to determine need to antibiotics • Check respiratory culture and treat if positive • Check CRP to determine need for Abx
Introducing Procalcitonin as a new biomarker • Proposed initially in 1991 for severe lung injury during Gulf War, review of the data showed those with severe sepsis or septic shock were high while those without infection were low • Meningitis in a pediatric hospital in Paris • Endotoxin response (3hrs, peak 6hrs, remained elevated for 24 hrs) • PCT has a short half-life (25-30 hrs) and levels decline rapidly with resolution of infection * Clinical Laboratory News, July 2009
Procalcitonin in a healthy individual Low PCT values in blood of healthy persons: median 12.7 pg/ml Morganthaler N. et al, Clin Lab 2002, 48;263-270
Procalcitonin in infection Alternative synthesis of PCT • Bacterial toxins (gram+/-) and cytokines stimulate production of PCT in all parenchymal tissues • PCT is immediately released into the blood stream • This process can be blocked by viral infections Adapted from Christ-Crain et al., 2005
Procalcitonin not elevated in viral infection • IFN-y is produced in viral infections and blocks the production of PCT Adapted from Christ-Crain et al., 2005
Diffuse PCT production in bacterial infection Muller B. et al. JCEM, 2001
1st algorithm for use of PCT to reduce Abx use • Christ-Crain et al 2004 Switzerland • Prospective randomized single-blinded • LRTI only • Threshold PCT of 0.25 ug/L to determine initiation of Abx therapy • PCT group had a 47% reduced rate of Abx exposure • No difference in lab or clinical outcomes
Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP), 2009 • Largest study examining use of procalcitonin for acute respiratory infections • Multicenter, noninferiority, randomized controlled trial of 1359 adults in 6 tertiary-care hospitals in Switzerland presenting to ED with suspected respiratory tract infection • Intervention: pts were randomized to standard guidelines vs PCT algorithm with predefined cutoff ranges for initiating or stopping Abx • All pts screened with PCT. If Abx withheld then PCT rechecked 6-24 hrs later. All hospitalized pts were clinically reassessed on days 3, 5, and 7 and at discharge
Control group – Up-to-Date Guidelines • Abx encouraged for 5-10d in uncomplicated CAP • 10d in necrotizing CAP • COPD abx 5-10d in severe GOLD IV or purulent sputum • Acute bronchitis, Abx not recommended • CRP and WBC were allowed to follow for resolution of infection • Choice of Abx was at discretion of provider in both groups
Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections, 2017 • Cochrane Review, 26 trials in 12 countries including 6708 participants • Primary care, ED, medical wards, and ICU setting • Acute respiratory infections including upper and lower tract (Including PNA, bronchitis, exacerbation of COPD, others) • Assigned to receive abx based on procalcitonin levels or a control group
73yo M with HTN and BPH presents to the ED with cough, fever, SOB • Temp: 37.2 • 121, 118/76, 26, O2 sat 86% on RA -> 98% on 2LNC • WBC 20, Lactate 5.4 -> 5.2 after 2L LR • CXR: Lingular opacity consistent with infectious process • Cefepime and Vancomycin IV in the ED • Severity index leads to admission to the ICU • Bcx end up being negative
When to stop antibiotics? • Convert to orals after 24 hours afebrile and stable vital signs, then complete for 14 total days • Continue until CRP <4 and normalized WBC • Check initial and daily procalcitonin and stop when decreased by ≥80%, and patient clinically improving • Check procalcitonin and stop when ≤0.5ug/L • Let the patient’s PCP figure it out
Neonatal sepsis CRP 71% 88% 85% PCT 85% 84% 91% CRP+PCT 81% 89% 96% Ruan et al., 2018
Growing body of evidence! Sager et al., 2017
PCT levels may be falsely ELEVATED in: PCT levels may be falsely LOW in: Contained infections (abscess, empyema) Infection from bacteria lacking a cell wall (M. pneumoniae, C. pneumoniae) PCT drawn too early in infection process Severe immunosuppression other than corticosteroids • ESRD/Hemodialysis • Severe Trauma • Prolonged circulatory shock • Surgery • Burns • Pancreatitis • IVIG treatment • Acute GVHD • Malaria and some fungal infections • Medullary thyroid carcinoma • Heatstroke • Neonates < 48hours
Take Home Points • PCT is found in very low levels in normal healthy adults and produced in the C-cells of the thyroid. During infection PCT is released from the entire body • Viral infections inhibit PCT • PCT-guided Abx initiation and discontinuation in LRTIs is non-inferior to the standard of care and decreases exposure and side effects of Abx, but also reduces 30-day mortality as shown in Cochrane review • PCT-guided Abx discontinuation in Critically ill patients in the ICU, decreased Abx exposure and was non-inferior to standard treatment regarding mortality • Adding PCT to CRP improved the accuracy of diagnosing Sepsis in neonates compared to CRP alone • Future studies will explore uses of PCT in other site specific body areas • PCT can assist a provider but not replace clinical intuition or override a patient’s clinical condition • PCT levels can be falsely high or low in certain clinical circumstances
Resources Bohuon, C. A Brief History of Procalcitonin. Intensive Care Med 2000;26 Boudama et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicenter randomized controlled trial. Lancet 2010;375 Christ-Crain et al. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly2005;135 de Jong et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomized, controlled, open-label trial. Lancet Infect Dis 2016;16 Kootenai Health. Procalcitonin (PCT) Protocol for Antibiotic Guidance in Respiratory Tract Infections. Protocols. 2017:1-6 Morganthaler N. et al. Detection of Procalcitonin (PCT) in health controls and patients with local infection by a sensitive ILMA. Clin Lab 2002, 48;263-270 Muller et al. Ubiquitous expression of the calcitonin-I gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab2001; 86 Rhee, Chanu. Using Procalcitonin to Guide Antibiotic Therapy. OFID 2016:1-10 Ruan et al. The combination of procalcitonin and C-reactive protein or presepsin alone improves the accuracy of diagnosis of neonatal sepsis: a meta-analysis and systematic review. Critical Care 2018;22:316 Sager et al. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Medicine 2017;15:15 Schuetz et al. Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections. JAMA 2009;302:10 Schuetz et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections (Review). Cochrane Data Base of Systematic Reviews 2017;10 Shehabi et al. Procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. A randomized controlled trial. Am J Respir Crit Care Med 2014;190