Sepsis biomarkers an update by Dr Puneet Jain
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The document discusses the importance of biomarkers in diagnosing and managing sepsis, highlighting their role in personalizing treatment due to the absence of a gold standard for sepsis diagnosis. It classifies various biomarkers based on their diagnostic, prognostic, and theranostic capabilities, noting the potential benefits and limitations of commonly used markers like CRP and procalcitonin. The author emphasizes the necessity for a combined approach using multiple biomarkers to improve diagnosis and patient outcomes.
Sepsis biomarkers an update by Dr Puneet Jain
- 1. Sepsis biomarkers: an update Dr Puneet Jain MD (Pediatrics) PGIMER, IDPCCM (PGIMER) DM (Pediatric Critical Care) JIPMER PICU incharge, Assistant Professor, Pacific Medical College, Consultant Intensivist, Bhandari Children Hospital Udaipur, Rajasthan 1
- 2. Learning objective Sepsis pathophysiology Biomarker and its classification Evidence and clinical application Combination of biomarkers approach Biomarkers Future Perspectives
- 3. Introduction 3 Identifying organisms by culturing appropriate specimens in the context of clinical suspicion remains the recommended method for diagnosing infection
- 4. Therapeutic conundrum for ICU clinician 4 -Initiation of effective antibiotics within 1 Hour -Widespread use of broad-spectrum antibiotics -No single, rapid, and accurate diagnostic test -The drug sensitivity results ,not available for 24 to 72 hours -Antibiotic stewardship
- 5. Why are biomarkers needed ⊳ No gold standard to diagnose sepsis ⊳ No tool to select, evaluate, and de-escalate treatment ⊳ No reliable way to predict outcome ⊳ Biomarkers can be the key to personalized medicine in sepsis whereby patients receive tailored treatment based on their unique characteristics 5
- 6. What is a Biomarker? “…a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” -Group BDW. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics. 2001; 37:2290–2298. 6
- 8. Research in the field of biomarkers 8 8Fig. Articles published on biomarkers in sepsis.
- 9. 01 Diagnostic Distinguish infectious v/s non infectious Causative organism and antibiotic stewardship 02 Prognostic Assigning risk profiles Predict outcome 03 Theranostic Stratification Evaluate specific therapies Key to personalized medicine Classification of biomarkers Crit Care Clin 34 (2018) 139–152
- 10. 10Crit Rev Clin Lab Sci, 2013; 50(1): 23–36
- 11. Biomarkers of Sepsis Biomarkers of organ dysfunction • ANP • BNP • Troponin • Protein S 100B • Surfactant Protein • NSE • GST Cytokines/Che mokines/Cell surface markers • IL-1 • IL-6 • IL-10 • IL-8 • IL-12 • MCP • TNF • MIP1,2 • CD 10, 25, 48, 64 Endothelial damage markers/Coagulatio n markers • ADAM TS 13 • Selectins • vWF • aPTT • FDP • Fibrin • Protein C and S Receptor biomarkers • CCR • TLR • TNF alpha • sTREM-1 Acute phase reactants • CRP • Procalcitonin • Ferritin • Pentraxin 3 • LBP • Ceruloplasmin • SAA Critical Care 2010
- 12. Ideal biomarker characteristics 4 Point of care test 1 Fast kinetics 2 Low cost Short turnaround time 3 Linked to main underlying process 5 High sensitivity and specificity
- 13. ROC and AUROC 13 AUROC values: ⊳ .90-1 = excellent (A) ⊳ .80-.90 = good (B) ⊳ .70-.80 = fair (C) ⊳ .60-.70 = poor (D) ⊳ .50-.60 = fail (F)
- 14. Case scenario N 4 Yrs/F ⊳ c/o high grade fever for 3 days ⊳ Generalized blanchable rashes ⊳ Mild pedal edema ⊳ Tachycardia, tachypnea ⊳ Received IV antibiotics in prev hospital for 2 days 14
- 15. How to proceed? ⊳ Possibilities ▸ Sepsis ▸ Inflammatory disorder Initial management ⊳ IV antibiotics/symptom atic t/t 15 Day 1 Hb 10 TLC 18800 DLC 77%/22% Platelets 103000 CRP 86 (0-6) LFT Normal RFT Normal MP/Dengue/scr ub Negative
- 16. CRP ⊳ Acute phase protein ⊳ Blood levels dramatically increase with tissue injury, infection, and acute severe inflammatory states ⊳ The protein synthesis and secretion of CRP is IL-6 driven 16
- 17. CRP: Strengths Peaks 36 - 50 hours after an inflammatory trigger Reflect the magnitude of the inflammatory stimulus and sepsis severity Easily available and low cost Serial use for therapeutic response assessment Not affected by immunosuppression, renal dysfunction or corticosteroid use 17
- 18. CRP: can it discriminate patients with and without infection 18
- 19. CRP: Can it be used to assess the adequacy of therapy 19
- 20. CRP: as a predictor of mortality in critically ill patients 20
- 21. CRP for antibiotic stewardship ⊳ To guide duration of antibiotic therapy ⊳ Can suggest ineffective initial antibiotic therapy ⊳ Reduce unnecessary antibiotic usage 21
- 22. Coming back to the case 22 86 124 117 82 98 87 0 20 40 60 80 100 120 140 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 CRP CRP
- 23. Limitations of CRP measurement ⊳ CRP lacks specificity ⊳ Increased in other inflammatory and all infectious disorders ⊳ Low levels of CRP should be interpreted with caution in patients with fulminant hepatic failure 23
- 24. Procalcitonin: Vital Statistics 24 ⊳ Levels rise within 4-6 hours of infection ⊳ Peaks after 12-30 h ⊳ PCT has a half-life of 24 h ⊳ fall similarly quickly upon resolution of infection
- 25. Procalcitonin: potential Discriminating between infectious and non-infectious inflammation To differentiate between viral and bacterial infections Indicate the presence of bacterial super infection in patients with viral diseases Gram-negative bacteraemias >>>Gram positive bacteraemias 25
- 26. Procalcitonin in bacterial infection: Diagnostic value 26 Interdisciplinary Perspectives on Infectious Diseases 2009
- 28. 28
- 29. 29 Clinical Pediatrics 2017, Vol. 56(9) 821– 827
- 30. Procalcitonin as a prognostic biomarker 30
- 31. PCT: can it be used to shorten the duration of antibiotics? 31
- 32. 32
- 33. 33
- 34. 34
- 35. Procalcitonin response to effective treatment 35
- 36. Coming back to the case 36 0 10 20 30 40 50 Procalcitonin Procalcitonin 86 124 117 82 98 87 0 20 40 60 80 100 120 140 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 CRP CRP
- 37. 37
- 38. The role of PCT in antibiotic stewardship ⊳ Extremely attractive in the current climate of increasingly antibiotic resistant microbes ⊳ Antibiotics can be safely stopped based on serial PCT measurements ⊳ Avoidance of antibiotic initiation ⊳ Reduction of antibiotic course length 38
- 39. Are there any clinical situations which would not benefit from a PCT test? 39J Anesth 2012
- 40. Different features of CRP and PCT ⊳ CRP Rises slower than CRP Relatively delay in diagnosis PCT Rises quickly Allows anticipation of a diagnosis of sepsis 24-48 hours before the CRP level would
- 41. Different features of CRP and PCT 41 ⊳ PCT PCT rises in proportion to the severity of sepsis and reaches its highest levels in septic shock PCT concentrations more rapidly declines as compared with CRP CRP CRP levels may not further increase during more severe stages of sepsis CRP remains high even in the late stage of disease
- 42. Combination of PCT and CRP 42
- 43. 43 Fungi-related sepsis, even severe sepsis or septic shock, does not necessarily elicit a substantial increase in serum PCT
- 44. Biomarkers for Fungal infection
- 45. Which patient should be tested? When and how the test should be performed 45
- 46. ⊳ 4 year /M ⊳ Severe pneumonia ⊳ Blood c/s :Nil ⊳ Swine Flu: Neg ⊳ MP/Scrub: Neg ⊳ CBC: Worsening leucopenia/Neut ropenia ⊳ CRP: High ⊳ Procalcitonin: Normal ⊳ Biofires: AdenovirusGalactomannan : Positive Case
- 47. Utility of fungal markers ⊳ To precise the diagnosis ⊳ For early detection of IA in the absence of clinical signs or symptoms ⊳ Assessment of therapeutic response 47
- 48. IL-6 ⊳ Mediates the initial response of the innate immune system to injury or infection 48
- 49. IL-6: Prediction of severity of sepsis 49 IL-6: Predictor of mortality
- 50. . EMBO Mol Med 2020
- 51. EMBO Mol Med 2020
- 52. Case scenario ⊳ 10 year/M ⊳ High grade fever/dyspnea ⊳ Covid positive ⊳ CRP: High ⊳ Procalcitonin: normal ⊳ IL 6: 196 pg/ml ⊳ Disease exacerbation ⊳ CRP : Rebounded ⊳ Procalcitonin: increased ⊳ IL-6: Normal (after t/t) 52 At admission Day 8
- 53. Lactate ⊳ Not specifically approved for sepsis ⊳ Lactate levels have been a useful marker for organ dysfunction ⊳ A endpoint for resuscitation in patients with sepsis and septic shock 53
- 54. 54 Lactate clearance ⊳ Lactate clearance is defined as the percent of change in the lactate level per hour from the baseline measurement ⊳ Calculated using the equation (Initial lactate level - follow-up lactate level) 100 Initial lactate level
- 55. Neutrophil-Lymphocyte Ratio (NLR): Free upgrade to your WBC 55
- 56. 56Lowsby R, et al. Emerg Med J 2014;
- 57. Combination of markers approach ⊳ No single marker may be able to have the high accuracy ⊳ Search for a single “magic bullet ”marker might ultimately be fruitless ⊳ A combination of markers could improve diagnosis, prognosis and treatment efficacy, and thereby survival 57
- 58. Bioscore AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 186 2012 PCT 0 1 sTREM-1 0 1 PMN CD64 Index 0 1
- 59. 59 Critical Care 2007, 11:R38
- 60. PERSEVERE Model (The pediatric sepsis biomarker risk model) 60 The pediatric sepsis biomarker risk model (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl) reliably identifies children at risk of death and greater illness severity from pediatric septic shock. Wong et al. Critical Care 2012,
- 61. 61 Where are we now?
- 63. 01 Should I start antibiotics? . 02 Viral or bacterial infection 03 How to follow up the patient 04 When to change therapy 05 Viral infection with hyper inflammation . 06 When to stop antibiotics Clinical decision PCT CRP/PCT Trend Rising trend PCT preferably IL-6 PCT CRP PCT PREFERABLY/ CRP Child with febrile illness: Biomarker utilization
- 64. To simplify: Biomarkers approach ⊳ Persistent fever ⊳ evidence of single or multi-organ dysfunction ⊳ additional features. This may include children fulfilling full or partial criteria for KD ⊳ Hematological malignancy/ post transplant/BM suppression ⊳ Clinical suspicion/radiological evidence ⊳ Not improving with antibiotics ⊳ Persistent fever ⊳ Cytopenias ⊳ Organomegaly ⊳ Atypical course A child presenting with Atypical febrile illness CBC, CRP, Ferritin, D Dimer Troponin, BNP CBC, CRP, PCT, Galactomannan, 1,3 BDG CBC, CRP, PCT, Ferritin, TG, LDH, Fibrinogen
- 65. 65 Conclusion The clinical use of biomarkers in sepsis is still at its infancy Helpful in diagnosis and to monitor therapeutic interventions . Should be used an adjunctive diagnostic tool to clinical judgment, culture and available lab clues . No singular 'ideal' biomarker, a more effective, alternative strategy may be to combine multiple markers.
Editor's Notes
- #4: Sepsis is characterized by complex pathophysiology and heterogeneous phenotypes of affected patients regarding their symptoms, response to treatment, and outcomes. The diagnostic techniques for bloodstream infection available to most ICU clinicians today do not fundamentally differ from Robert Koch’s laboratory methods circa 1887.1,2 That was the year when 2 co-workers in Koch’s laboratory, Fanny Hess and Richard Petri, first suggested using semisolid agar and 2 glass plates of slightly different size for isolation of bacteria in pure culture
- #5: Sepsis guidelines mentions early administration of antibiotics, this leads to empirical use, broad spectrum antibiotics Antibiotic stewardship programs are focused on curbing excessive use of empiric antibiotics, placing the ICU clinician in a therapeutic conundrum
- #6: Basically what is needed is that a new generation of biomarkers that can clearly distinguish between infection-mediated organ dysfunction and sepsis mimics with non–infection-mediated systemic inflammation.
- #8: The Greek physician Hippocrates (460–370 BC) first described “sepsis” The idea of a sepsis biomarker came up in 1988, when Hoyt and colleagues23 reported lymphocyte changes to be predictive of sepsis. Because of the complex sepsis pathophysiology that comprises a large number of molecular mechanisms, more than 180 markers over the past decades have been identified as potential biomarkers of sepsis, of which only 20% were examined in studies for diagnostic use in sepsis.24 The most investigated biomarkers in sepsis are procalcitonin (PCT), C-reactive protein (CRP), interleukin (IL)-6, soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), presepsin, and lipopolysaccharide binding protein (LBP).
- #9: In a comprehensive systematic review, conducted nearly a decade ago, 178 biomarkers were evaluated in the context of sepsis. A crude search in the PubMed database shows that biomarkers in sepsis is a trending topic
- #10: Biomarkers that can discriminate sepsis from noninfectious critical illness or can differentiate between causative organisms in sepsis can be regarded as diagnostic biomarkers. A diagnostic biomarker can diminish improper use of antibiotics and could be used for antibiotic stewardship. Prognostic biomarkers can help predict outcomes in patients with sepsis by assigning risk profiles. In addition, biomarkers can aid in stratifying patients in subgroups based on specific pathophysiologic features, thereby paving the way to personalized therapy with biomarker-guided follow-up of response to treatment. The approach to using biomarker tests to select and evaluate specific therapies is known as theranostics and is seen as a main tool in the future management of many diseases.
- #11: Sepsis begins with either infection or tissue injury. PAMPs from invading organisms or DAMPs from injured tissue cells (or both) are recognized by macrophage receptors such as the TLRs. This results in the production of pro-inflammatory cytokines such as TNF, IL-1b and IL-6 and chemokines such as IL-8 and MCP-1. IL-6 stimulates the liver to produce CRP and complement proteins. Many cells in the body also produce PCT in response to both infection and injury
- #13: Linked to the main underlying processes –Inflammation –Coagulation –Tissue damage–Tissue repair Should be present at the onset or even before the appearance of the clinical signs of sepsis to have prognostic value
- #17: CRP levels in the blood can increase in sepsis and septic shock to greater than 10,000-fold greater resting levels
- #20: Figure 2. a. Time course of mean CRP concentration (mg/ dl) in group 1 (no change in antibiotics or deescalation) and group 2 (change in antibiotic or addition of another antibiotic class). Differences: p = 0.001. This prospective, observational, multicenter study included all critically ill patients with sepsis admitted to two medico-surgical departments of intensive care in Brussels, Belgium during a 5-month period. Patients were divided into three groups according to their clinical course: group 1 — patients with a favorable response to initial antibiotic therapy; group 2 — patients who required a change in antibiotic therapy; group 3 — patients who needed a procedure to control the infection. Results: CRP concentrations decreased more rapidly and to a greater degree in group 1 than in group 2 patients (p = 0.001). An increase in CRP of at least 2.2 mg/dl in the first 48 h was associated with ineffective Conclusion: Changes in CRP levels over the first 48 h of therapy can help to evaluate the response to initial antimicrobial therapy in septic patients.
- #21: The subgroup analysis showed that the weighted mean difference in early (within 48 hours) C-reactive protein levels between survivors and non-survivors was not significantly different, in contrast to the late (beyond 48 hours) C-reactive protein level. This was significantly greater in non-survivors with a weighted mean difference of 63.80 mg/l (95% confidence interval 35.67 to 91.93). Our systematic review shows that while the early C-reactive protein concentration is not a good predictor of survival in critically ill patients, the late C-reactive protein concentration may help to identify patients who are at risk of death.
- #25: Procalcitonin (PCT) is the precursor of calcitonin (CT) Whereas calcitonin is secreted exclusively by the C-cells of the thyroid after hormonal stimulation, PCT is produced by numerous cell types and organs after proinflammatory stimulation, especially when caused by bacterial infections. Increased PCT levels can be observed within 3 to 6 hours of an infectious challenge and rise with increasing severity of infection, making PCT an early and highly specific marker for severe systemic bacterial infection and sepsis. PCT returns to normal values of < 0.05 ng/mL as the severe bacterial infection resolves, with a half life of 24 hours. Normal serum values are below 0.05 ng/mL Values <0.5 ng/mL represent a low risk values of 0.5 - 2.0 ng/mL suggest an intermediate likelihood of sepsis and/or septic shock a value of 2.0 ng/mL suggests a significantly increased risk of sepsis and/or septic shock.
- #27: We studied the diagnostic accuracy of procalcitonin (PCT) as a biomarker for a bacterial cause of fever in a cohort of 157 consecutive travellers with fever after a stay in the (sub)tropics. Elevated procalcitonin levels were observed not only in about 50% of travellers with proven bacterial infection, but also in a significant proportion of travellers with a likely infection. Using a cutoff point of 0.5 ng/mL, procalcitonin had a sensitivity of 0.52 and a specificity of 0.76 for a bacterial cause of fever on admission. Interestingly, only 1 out of 16 patients with a proven viral infection had a marginally elevated PCT concentration on admission, suggesting that an increased PCT level likely excludes a viral infection as the cause of fever. However, the diagnostic accuracy of this semiquantitative procalcitonin test for a bacterial cause of fever on admission is too poor to advocate its use in the initial clinical evaluation of fever in a setting of ill-returned travellers. negative result or a PCT < 0. 5 ng/mL was classified as “normal ”; a PCT of 0.5 ng/mL or a PCT between 0.5– 2.0 ng/mL was classified as “low ”; a PCT of 2.0 ng/mL or a PCT between 2.0–10.0 was classified as “moderate ”; a PCT of 10.0 ng/mL and above 10 ng/mL was classified as “high ” as recommended
- #31: Serum PCT levels have also been noted to increase with increasing severity of sepsis and organ dysfunction.
- #33: This case demonstrates the ability of PCT to predict invasive disease (occult bacteremia) at a very early stage when other common biomarkers are still normal.
- #35: For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21∙2% [65/307] vs 20∙4% [64/314]; absolute diff erence 0∙8%, 90% CI –4∙6 to 6∙2) and day 60 (30∙0% [92/307] vs 26∙1% [82/314]; 3∙8%, –2∙1 to 9∙7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the
- #38: PCT is a useful marker not only of sepsis but also of severity of illness. We have demonstrated PCT increases according to disease severity from sepsis to septic shock.20 If PCT levels are increasing, as in the first 36 hours of our case, evolution is bad. The meningococcal infection was controlled by antibiotics, but the septic shock was not controlled, and PCT increased rapidly necessitating a therapeutic change. Following optimization of septic shock treatment, PCT levels decreased progressively indicating treatment was correct. Treatment based on daily PCT level changes may be initiated hours or days before the occurrence of clinical complications.
- #42: Therefore, the diagnostic capacity of PCT is superior to that of CRP due to the close correlation between PCT levels and the severity of sepsis and outcome.
- #47: Sepsis induced bone marrow suppression Hemato-oncologial disease Immunocompromised broad spectrum antibiotics Clinical suspicion Radiological evidence
- #49: IL-6 enhances production of the so-called acute phase reactants, including CRP IL-6 stimulates a shift in the production of cells in the bone marrow Serum levels of IL-6 have been shown to rise within 1 h and rapidly peaked within 2 h after the infectious stimulus The level of IL-6 usually increases earlier than that of PCT CRP and fever
- #51: IL-6 levels before and after treatment in three patient groups classified according to baseline IL-6 levels of ≥ 40 pg/ml (n = 11), ≥ 20 pg/ml (n = 6), or < 20 pg/ml (n = 9; left). Two representative chest computed tomography (CT) scans before and after treatment from each group (right).
- #52: IL-6 levels at diagnosis and after disease progression in three exacerbated patients (left). Progressed radiological findings were recorded in two patients (right), while radiological assessment after treatment was not performed in the third patient due to poor general condition.
- #56: pitfalls of NLR The following pitfalls should be noted: Exogenous steroid: May directly increase the NLR. Active hematologic disorder: Leukemia, cytotoxic chemotherapy, or granulocyte colony stimulating factor (G-CSF) may affect cell counts. HIV: Some studies have excluded patients with HIV. Overall the utility of NLR in this patient population remains unclear. Patients with advanced AIDS and chronic lymphopenia might be expected to have a higher baseline NLR.
- #59: The probability of sepsis increased together with the bioscore with rates of infection of 3.8% for a bioscore of 0–100% for a bioscore of 3
- #62: Even though numerous biomarkers for sepsis have been identified,8,10 the recently updated guidelines of the Surviving Sepsis Campaign only see a minor role for 1 biomarker in clinical practice; that is, procalcitonin (PCT). This limitation is largely attributed to the complex pathophysiology of sepsis, and it seems unlikely that a single biomarker can provide accurate information about the main drivers of the disturbed host response in individual patients with sepsis
- #66: The clinical use of biomarkers in sepsis is still at its infancy, especially compared with other fields such as vascular medicine and oncology Markers of inflammation/ infection can be helpful in diagnosis and to monitor effect of therapeutic interventions Biomarkers should be used an adjunctive diagnostic tool to clinical judgement, culture and other available laboratory clues No singular 'ideal' biomarker of sepsis has been identified; a more effective, alternative strategy may be to combine multiple markers , and while we are still far away from truly personalized medicine in the field, many of the established and emerging biomarkers are helpful in the daily care of septic patients Conclusion •Utility •Earlier detection of disease •Earlier detection of high risk sub-groups •Earlier recognition of treatment success •Earlier de-escalation •Adjunctive prognostication Future sepsis biomarker research requires multicentre studies, methodology standardization and more rigorous assays