Procalcitonin and other biomarkers for infectious disease Infectious - PDF document

2/6/2020 Procalcitonin and other biomarkers for infectious disease Infectious Diseases in Clinical Practice February 17, 2020 Bryn A Boslett, MD Assistant Clinical Professor University of California, San Francisco Disclosures • I have no financial disclosures • I will not discuss off ‐ label uses of medications or unapproved laboratory tests 1

2/6/2020 Content and Learning objectives • Discuss how biomarkers may be used to guide diagnosis of infection and antibiotic therapy • Define procalcitonin and explain it’s characteristics • Recognize the limitations of procalcitonin and other biomarkers as an effective tool for making treatment decisions Outline • Definition and assay characteristics • Lactate • ESR / CRP • Procalcitonin • Data for use of procalcitonin in sepsis • Data for use of procalcitonin in lower respiratory tract infection • Summary and recommendations 2

2/6/2020 Scope of the problem • Sepsis is diagnosed in 1.7 million adults per year • Bacterial infections account for ~50% of cases of sepsis • Clinicians cannot hold antibiotics while awaiting cultures, and cultures are not perfectly sensitive • A rapid, low cost assay that is both sensitive and specific for bacterial infection would be a welcome addition to sepsis diagnosis and management Intensive Care Med, 43 (2017), pp. 304 ‐ 377 Why use biomarkers? • as a diagnostic tool – “is this patient septic?” • as a tool for staging of disease severity – “how should we triage?” • as an indicator of prognosis – “what is the most likely outcome?” • for prediction and monitoring of clinical response to therapy – “how can we know if this is working?” 3

2/6/2020 Usual biomarkers for infection Biomarker Produced By Infectious Triggers Non ‐ infectious Triggers WBC Bone Marrow Any infection Surgery, steroids, (bacteria, viruses, neoplasia, trauma fungi, etc) CRP Liver Any infection; Autoimmune, IBD, endocarditis, surgery, trauma osteomyelitis Lactate Anaerobic Sepsis Trauma, surgery, metabolism burns, seizure, ischemia, DKA, toxic ingestion, cirrhosis Crit Care Med 2009; 37: 2093 ‐ 4. Mayo Clin Proc. 2013 Oct; 88(10): 1127–1140. Lactate levels correlate with mortality in sepsis J Trauma Acute Care Surg. 2012 Jun;72(6):1532 ‐ 5. 4

2/6/2020 Lactate is not specific for infection West J Emerg Med. 2017 Feb;18(2):258 ‐ 266. ESR and CRP Characteristic CRP ESR Function Activates complement, acts as Fibrinogen mediates coagulation an opsonin for various and inflammation pathogens Mechanism Dying cells release cytokines, Fibrinogen causes RBCs to clump, causing liver to produce CRP ESR is indirect measure Rate of rise Rapid rise 4 ‐ 6 hrs, peaks 1 ‐ 2 Slow rise, peaks 7 ‐ 10 days, half ‐ life days, normalizes 3 ‐ 7 days after of weeks after stimulus ends stimulus ends Specimen Serum/plasma, stable ~7 days Fresh whole blood, test same day needed Reproducibility High Low/moderate Contemporary Pediatrics, June 2002, p. 64+. Gale Academic Onefile, Accessed 8 Jan. 2020. 5

2/6/2020 Cleve. Clin. J. Med. 56:126 ‐ 130. Value of ESR/CRP for infectious diseases • When you suspect active infection, may be helpful to check and trend CRP • Normal value does not rule out infection, elevated level does not rule in Annals of the Rheumatic Diseases 2013;72:A1006. 6

2/6/2020 Procalcitonin • Procalcitonin (PCT): Peptide pre ‐ hormone of calcitonin • CT secreted by thyroid C ‐ cell as response to hypercalcemia • Normal PCT values negligible in healthy adults (< 0.05 ng/dl) J. Clin. Endocrinol. Metab. 79 (6): 1605–8. Lindscheid P et al. Endocrinology 2003; 144:5578 ‐ 84. Christ ‐ Crain M, Mueller B. Swiss Med Wkly 2005; 135: 451 ‐ 460. Procalcitonin discovery • 1983: calcitonin is elevated in toxic shock, bacterial meningitis • 1990: “calcitonin ‐ related peptide” elevated in sepsis • 1993: procalcitonin in sepsis • Produced by many body tissues in sepsis • Continuum of PCT level from no infection  mild infection  severe sepsis • Non ‐ infectious stimuli as well, but transient Lancet 8319: 294; J Lab Clin Med 101: 576; Surgery 108: 1097; Lancet 8844: 515; Arth Rheum 40: 1250 7

2/6/2020 Mechanism • Bacterial infection  IL ‐ 1, IL ‐ 6, and tumor necrosis factor ‐α  stimulates PCT production • Viral infection  interferon ‐γ  no stimulation of PCT Lindscheid P et al. Endocrinology 2003; 144:5578 ‐ 84 Christ ‐ Crain M, Mueller B. Swiss Med Wkly 2005; 135: 451 ‐ 460 Open Forum Infect Dis. 2015 Sep; 2(3): ofv098.Published online 2015 Jul 3. Characteristics • Rises at 3 – 6 hrs, peaks 12 ‐ 24 hrs • Correlated with infection severity • Levels decline 50% over 24 hours • Assay time ~30 mins • Cost ~$25 Muller B et al. J Clin Endocrinol Metab 2001; 86: 396 ‐ 404 Best Pract Res Clin Endocrinol Metab. 2001 Dec;15(4):553 ‐ 73. 8

2/6/2020 Reasons for inaccurate result False Negatives False Positives • Severe stress • Very early infection • Birth • Intracellular bacteria • Trauma/post ‐ op • Mycoplasma • Burn • Legionella • Non ‐ bacterial cytokine storm • Localized / indolent infection • Malaria • Subacute bacterial • Systemic fungal infection endocarditis • GVHD • Occult abscess • Dysregulated PCT • Osteomyelitis • Meds (IL ‐ 2, Anti ‐ thymocyte globulin) • Paraneopalstic (carcinoid, medullary thyroid, SCLC, etc) Christ ‐ Crain M, Mueller B. Swiss Med Wkly 2005; 135: 451 ‐ 460. Procalcitonin – rationale for use Procalcitonin can aid decisions about antimicrobial initiation and/or de ‐ escalation Redundant Spectrum not coverage indicated 4% 10% Noninfectious or nonbacterial 33% Adjustment not made 3% Duration too long Colonization or 34% contamination 16% Hecker MT et al . Arch Intern Med. 2003;163:972 ‐ 978. 9

2/6/2020 Where Data Exists for PCT BMC Med. 2011; 9: 107. . Published online 2011 Sep 22. doi: 10.1186/1741-7015-9-107 Clinical setting for PCT use Setting Abx initiation Abx duration, days median (IQR) Overall 64% vs 84% 7 (4–10) vs 10 (7–13) Outpatient* 23% vs 63% 7 (5–8) vs 7 (6–8) ED 73% vs 88% 7 (4–10) vs 10 (7–12) ICU 100% vs 100% 8 (5–15) vs 12 (8–18) *Mainly trials of URI, bronchitis, COPD exacerbation Mitsuma SF et al. Clin Infect Dis 2013; 56(7):996 ‐ 1002 Schuetz P etal. Arch Int Med 2011; 171(15):1322 ‐ 31 10

2/6/2020 Procalcitonin – ICU • PCT >1 ng/mL had sensitivity 89%, specificity 94% for the diagnosis of sepsis (PPV 94%, NPV 90%) in the ICU PPV NPV (%) (%) PCT 94 90 CRP 74 75 IL ‐ 6 71 74 Lact 58 61 Muller et al. Crit Care Med. 2000 Apr;28(4):977 ‐ 83. 2007: PCT to diagnose sepsis Tang, AE. Lancet Infect Dis. 2007 Aug;7(8): author reply 502 ‐ 3. 11

2/6/2020 2013: PCT to diagnose of sepsis • 30 studies, 3244 patients • Pooled sensitivity was 0 ∙ 77 (95% CI 0 ∙ 72–0 ∙ 81) and pooled specificity was 0 ∙ 79 (95% CI 0 ∙ 74–0 ∙ 84) Lancet Infect Dis, 13 (2013), pp. 426 ‐ 435 PCT to trend treatment response in severe sepsis Clin Infect Dis. 2001;32:1718 ‐ 1725. 12

2/6/2020 PRORATA • Multicenter RCT ~600 ICU patients • Primary endpoint: all ‐ cause mortality and antibiotic ‐ free days Bouadma L et al. Lancet. 2010;375:463–474. PRORATA Bouadma L et al. Lancet. 2010;375:463–474. 13

2/6/2020 PRORATA Bouadma L et al. Lancet. 2010;375:463–474. PRORATA • 23% relative reduction in days of antibiotic exposure • Antibiotic ‐ sparing mainly obtained by shortening duration PCT group Control group Between group (n=307) (n=314) abs difference Days without Abx 14.3 (9%) 11.6 2.7 (p<0.0001) Days of Abx exposure 653 812 ‐ 159 (per 1000 inpt days) (p<0.0001) Bouadma L et al. Lancet. 2010;375:463–474. 14

2/6/2020 PCT for lower respiratory tract infections (LRTIs) Clin Infect Dis. 2017 Jul 15; 65(2): 183–190. Early data for PCT use for LRTIs • 2004: PCT reduces antibiotic prescriptions for lower respiratory tract illnesses (LRTI) by 40% • 2006: PCT reduces antibiotics for COPD (65%) and CAP (30%) • No increase in adverse events Christ ‐ Crain M et al. Lancet. 2004 Feb 21; 363(9409):600 ‐ 7. Christ ‐ Crain M et al. Am J Respir Crit Care Med. 2006 Jul 1; 174(1):84 ‐ 93. Stolz D. Chest. 2007 Jan; 131(1):9 ‐ 19. 15

2/6/2020 Pro ‐ HOSP Study • RCT of 1360 hospitalized adults with lower resp tract infection Schuetz P et al. JAMA. 2009 Sep 9;302(10):1059 ‐ 66. PCT reduced antibiotic use for all forms of LRTI • CAP: 32% abx reduction • COPD: 50% abx reduction • Bronchitis: 65% abx reduction • No difference in mortality, ICU admission, or complications Schuetz P et al. JAMA. 2009 Sep 9;302(10):1059 ‐ 66. 16

2/6/2020 Pro ‐ VAP Study • RCT of 100 pts treated for vent ‐ associated pneumonia • 27% reduction in antibiotic therapy in PCT group (15  10d) 1 1 2 2 3+ 3+ Stolz D et al. Eur Respir J (2009). Pro ‐ ACT study • 14 hospitals with “high adherence” to QI measures for pneumonia • ED and inpatient clinicians educated about the use of PCT for LRTI • Patients presenting with suspected LRTI then randomly assigned to serial PCT (with antibiotic use guideline) or standard care N Engl J Med 2018; 379:236 ‐ 249 17

2/6/2020 PCT failed to influence antibiotic use in ED or hospital N Engl J Med 2018; 379:236 ‐ 249 A focus on mortality data • 2018 systematic review and meta ‐ analysis • 26 randomized trials and 6708 patients Lancet Infect Dis. 2018 Jan;18(1):95 ‐ 107. 18