Biomarkers in Systemic Disease: What Actually Helps at the Bedside?

Procalcitonin, Troponin, IL-6, Ferritin — Separating Hype from Reality

Dr Neeraj Manikath , claude.ai

Abstract

Background: The proliferation of biomarkers in critical care has promised personalized medicine and improved outcomes, yet their clinical utility remains variable. This review critically evaluates four commonly used biomarkers—procalcitonin, troponin, interleukin-6, and ferritin—in the context of systemic disease management.

Methods: We reviewed current literature focusing on evidence-based applications, limitations, and practical considerations for each biomarker in critically ill patients.

Results: While these biomarkers offer valuable diagnostic and prognostic information, their interpretation requires understanding of physiological context, confounding factors, and integration with clinical assessment. Each marker has specific strengths and significant limitations that must be recognized for optimal utilization.

Conclusions: Biomarkers should complement, not replace, clinical judgment. Understanding their biology, kinetics, and limitations is essential for appropriate bedside application in critical care.

Keywords: Biomarkers, Critical Care, Procalcitonin, Troponin, Interleukin-6, Ferritin, Sepsis, Systemic Inflammation

Introduction

The modern intensive care unit is awash with biomarkers, each promising to unlock the mysteries of critical illness and guide therapeutic decisions. From the traditional complete blood count to sophisticated inflammatory mediators, these laboratory values have become integral to our daily practice. However, the gap between biomarker promise and clinical reality often leaves practitioners questioning their utility.

The challenge lies not in the absence of biomarkers, but in their appropriate interpretation and application. Four biomarkers—procalcitonin (PCT), troponin, interleukin-6 (IL-6), and ferritin—exemplify this challenge. Each has garnered significant attention, spawned numerous studies, and influenced guidelines, yet their bedside utility remains nuanced and often misunderstood.

This review aims to provide critical care physicians with a practical, evidence-based approach to these biomarkers, emphasizing their strengths, limitations, and appropriate clinical applications while debunking common misconceptions.

Procalcitonin: The Bacterial Infection Detective

Biology and Physiology

Procalcitonin, the precursor of calcitonin, is normally produced by thyroid C-cells in minute quantities (<0.05 ng/mL in healthy individuals). During bacterial infections, extrathyroidal tissues—particularly hepatocytes, monocytes, and neuroendocrine cells—dramatically increase PCT production in response to bacterial endotoxins and inflammatory cytokines, particularly tumor necrosis factor-α and interleukin-1β.¹

The kinetics of PCT are clinically relevant: levels rise within 2-4 hours of bacterial invasion, peak at 12-48 hours, and have a half-life of approximately 24 hours, making it useful for both diagnosis and monitoring treatment response.²

Clinical Applications: What Works

Sepsis Diagnosis and Differentiation PCT excels in differentiating bacterial from viral infections, with cut-off values of 0.25 ng/mL showing reasonable sensitivity (85%) and specificity (70%) for bacterial infection.³ However, the real clinical utility lies in serial measurements rather than single values.

Antibiotic Stewardship Perhaps PCT's greatest contribution is in antibiotic de-escalation. The PRORATA study demonstrated that PCT-guided antibiotic discontinuation reduced antibiotic exposure by 23% without increasing mortality.⁴ A declining PCT by >80% from peak or absolute values <0.25 ng/mL supports antibiotic discontinuation in appropriate clinical contexts.

Limitations and Pitfalls

The False Positive Trap PCT elevation occurs in numerous non-bacterial conditions:

Severe trauma and burns (cytokine release)
Post-cardiac arrest syndrome
Acute pancreatitis
Cardiogenic shock
Major surgery (peaks 24-48 hours post-operatively)

The False Negative Reality Low PCT doesn't exclude bacterial infection in:

Immunocompromised patients
Localized infections without systemic involvement
Early infection (<6 hours)
Certain bacterial species (Mycoplasma, Legionella)

Clinical Pearls

Pearl 1: Use PCT trends, not absolute values. A rising PCT despite appropriate antibiotics suggests treatment failure or complications.

Pearl 2: In post-operative patients, expect PCT elevation for 48-72 hours regardless of infection status.

Oyster 1: Don't use PCT as the sole criterion for antibiotic initiation—clinical assessment remains paramount.

Hack: In ventilator-associated pneumonia, PCT <0.25 ng/mL on day 3 of appropriate therapy strongly suggests treatment success.

Troponin: Beyond the Heart

Biology and Cardiac Specificity

Cardiac troponins (cTnI and cTnT) are regulatory proteins unique to cardiac myocytes, released during myocardial injury regardless of mechanism. High-sensitivity assays (hs-cTn) can detect minute amounts of myocardial damage, revolutionizing our understanding of cardiac injury in critical illness.⁵

Applications in Critical Care

Type 2 Myocardial Infarction In critically ill patients, troponin elevation often represents supply-demand mismatch rather than coronary thrombosis. Recognizing Type 2 MI is crucial as management differs significantly from Type 1 MI.

Prognostication Elevated troponin in sepsis, pulmonary embolism, and other systemic conditions consistently predicts worse outcomes, independent of traditional risk factors.⁶ This reflects the heart's role as a vital organ barometer during systemic stress.

Cardiac Dysfunction Assessment In conjunction with echocardiography, troponin helps identify septic cardiomyopathy and guides hemodynamic management strategies.

The Critical Care Context

Renal Dysfunction Both cTnI and cTnT accumulate in renal failure, but cTnT shows greater elevation. In dialysis patients, chronic cTnT elevation (often 0.05-0.2 ng/mL) represents baseline, and acute changes are more meaningful than absolute values.⁷

Right Heart Strain Troponin elevation in pulmonary embolism correlates with right heart dysfunction and identifies patients requiring more aggressive therapy, including thrombolysis consideration.

Interpretation Challenges

Kinetic Considerations Traditional troponin kinetics (rise at 3-6 hours, peak at 12-24 hours, normalize in 7-14 days) apply to Type 1 MI. In critical illness, patterns vary significantly based on the underlying pathophysiology and ongoing injury.

Clinical Context Integration Troponin elevation without typical ischemic symptoms requires careful evaluation:

ECG changes suggesting acute coronary syndrome
Wall motion abnormalities on echocardiography
Clinical presentation consistent with ACS

Clinical Pearls

Pearl 3: In sepsis, troponin elevation >0.6 ng/mL significantly increases mortality risk and should trigger enhanced cardiac monitoring.

Pearl 4: Rising troponin in the absence of coronary intervention suggests ongoing myocardial injury requiring investigation.

Oyster 2: Don't reflexively anticoagulate all patients with elevated troponin—determine the mechanism first.

Hack: Use the troponin/creatinine ratio in renal patients: values >100 suggest acute cardiac injury beyond chronic kidney disease effects.

Interleukin-6: The Inflammatory Orchestra Conductor

Biological Role

IL-6 is a pleiotropic cytokine central to innate and adaptive immunity, produced by various cells including macrophages, T-cells, endothelial cells, and fibroblasts. It orchestrates the acute-phase response, promotes B-cell differentiation, and influences hepatic protein synthesis.⁸

Unlike other inflammatory markers, IL-6 has a short half-life (1-7 hours) and rapidly reflects changes in inflammatory status, making it an attractive real-time biomarker of systemic inflammation.

Clinical Applications

Early Sepsis Detection IL-6 rises earlier than traditional markers like C-reactive protein, with levels >1000 pg/mL suggesting severe sepsis or septic shock.⁹ Its rapid kinetics make it valuable for early detection and monitoring therapeutic response.

Cytokine Release Syndrome IL-6 is the primary biomarker for CRS in CAR-T therapy, with levels >1000 pg/mL indicating severe CRS requiring tocilizumab therapy.¹⁰ This represents one of the most evidence-based applications of IL-6 measurement.

Prognostication in COVID-19 During the COVID-19 pandemic, IL-6 emerged as a powerful predictor of severe disease and mortality, with levels >80 pg/mL associated with increased ICU admission and death.¹¹

Limitations in Clinical Practice

Lack of Specificity IL-6 elevation occurs in numerous conditions:

Any systemic inflammatory state
Major trauma and surgery
Burns
Pancreatitis
Malignancy
Autoimmune diseases

Technical Challenges IL-6 measurement requires specialized assays not universally available. Sample handling is critical due to the cytokine's instability, and results may not be available in time for acute decision-making.

Cost-Effectiveness Concerns The high cost of IL-6 assays limits routine use, requiring careful consideration of clinical scenarios where the information will change management.

Emerging Applications

Immunoparalysis Detection Persistently elevated IL-6 combined with low HLA-DR expression on monocytes may identify patients with immunoparalysis who could benefit from immunostimulatory therapy.¹²

Personalized Anti-Inflammatory Therapy IL-6 levels guide tocilizumab therapy in CRS and may inform anti-inflammatory interventions in other critical conditions.

Clinical Pearls

Pearl 5: IL-6 >1000 pg/mL in early sepsis indicates high likelihood of organ dysfunction development.

Pearl 6: Declining IL-6 levels predict recovery better than absolute values.

Oyster 3: Don't use IL-6 as a screening test—reserve for specific clinical scenarios where results will influence therapy.

Hack: In resource-limited settings, use IL-6/albumin ratio as a poor man's inflammatory index—values >200 suggest severe systemic inflammation.

Ferritin: The Iron-Clad Inflammatory Marker

Beyond Iron Storage

While classically known as an iron storage protein, ferritin functions as an acute-phase reactant and damage-associated molecular pattern (DAMP) molecule. Serum ferritin levels reflect not only iron stores but also inflammatory activity, tissue damage, and immune activation.¹³

Clinical Applications in Critical Care

Hemophagocytic Lymphohistiocytosis (HLH) Ferritin >500 μg/L is a diagnostic criterion for HLH, with extremely high levels (>10,000 μg/L) strongly suggesting this life-threatening condition.¹⁴ In critical care, secondary HLH often masquerades as severe sepsis.

COVID-19 Severity Assessment Ferritin emerged as a powerful predictor of COVID-19 severity, with levels >1000 μg/L associated with increased mortality and need for mechanical ventilation.¹⁵ The mechanism likely involves both iron dysregulation and inflammatory hyperactivation.

Iron Overload Syndromes In patients receiving multiple transfusions, ferritin levels guide iron chelation therapy, though interpretation requires consideration of concurrent inflammation.

The Inflammatory Confound

Acute-Phase Response Ferritin levels can increase 10-100 fold during inflammatory states, making iron status assessment challenging in critically ill patients. The ferritin/transferrin saturation ratio helps differentiate inflammatory vs. iron-mediated elevation.

Tissue Damage Hepatocellular injury, rhabdomyolysis, and other tissue damage syndromes cause ferritin release independent of iron status or inflammation, complicating interpretation.

Specific Critical Care Contexts

Sepsis and MODS Ferritin levels correlate with organ dysfunction severity in sepsis, with values >1000 μg/L associated with increased mortality. However, the correlation reflects disease severity rather than providing specific therapeutic guidance.¹⁶

Acute Liver Failure Extremely high ferritin levels (>3000 μg/L) in acute liver failure suggest worse prognosis and potential need for transplantation evaluation.

Clinical Pearls

Pearl 7: Ferritin >10,000 μg/L should prompt HLH evaluation, especially in patients with unexplained multi-organ failure.

Pearl 8: In sepsis, ferritin trends matter more than absolute values—persistently rising levels suggest ongoing tissue damage or inadequate source control.

Oyster 4: Don't use ferritin alone to diagnose iron deficiency in critically ill patients—it's unreliable in inflammatory states.

Hack: Calculate the ferritin/log(ferritin) ratio: values <1.5 suggest hyperferritinemia syndrome requiring investigation for HLH or adult Still's disease.

Integration and Clinical Decision-Making

The Multi-Biomarker Approach

No single biomarker provides complete diagnostic or prognostic information. The art lies in integrating multiple markers with clinical assessment:

Sepsis Evaluation:

PCT for bacterial probability and antibiotic guidance
IL-6 for early detection and severity assessment
Troponin for cardiac involvement
Ferritin for overall inflammatory burden

Prognostic Assessment: Combining biomarkers improves prognostic accuracy:

PCT + lactate for sepsis mortality prediction¹⁷
Troponin + NT-proBNP for cardiac risk stratification¹⁸
IL-6 + ferritin for cytokine storm identification

Temporal Considerations

Understanding biomarker kinetics is crucial:

Early phase (0-6 hours): IL-6 rises first
Acute phase (6-24 hours): PCT and troponin peak
Sub-acute phase (24-72 hours): Ferritin continues rising
Resolution phase (>72 hours): All markers should decline with appropriate therapy

Economic Considerations

Biomarker testing incurs significant costs. Rational use requires:

Clear clinical questions that testing will answer
Potential for results to change management
Consideration of test characteristics in the specific population
Integration with institutional protocols and guidelines

Practical Guidelines for Bedside Application

When to Order

Procalcitonin:

Suspected bacterial infection with unclear diagnosis
Antibiotic stewardship decisions
Monitoring treatment response in severe infections

Troponin:

Suspected acute coronary syndrome
Risk stratification in sepsis, PE, or other systemic conditions
Evaluation of unexplained hemodynamic instability

IL-6:

Suspected cytokine release syndrome
Early sepsis detection when rapid results available
Research protocols or specialized inflammatory conditions

Ferritin:

Suspected HLH or hyperferritinemia syndrome
Iron status assessment (with caveats in inflammation)
Prognostic assessment in severe inflammatory conditions

Interpretation Framework

Consider the clinical context: Patient population, timing, concurrent conditions
Understand normal variations: Age, sex, comorbidities affect baseline values
Use appropriate cut-offs: Population-specific and indication-specific thresholds
Monitor trends: Serial measurements often more valuable than single values
Integrate with clinical assessment: Biomarkers supplement, don't replace, clinical judgment

Future Directions and Emerging Biomarkers

Point-of-Care Testing

Rapid, bedside biomarker testing is expanding, with PCT and troponin already available on many platforms. This accessibility improves clinical utility but requires understanding of platform-specific characteristics and limitations.

Novel Biomarkers

Emerging markers show promise:

Presepsin: May differentiate bacterial from viral infections better than PCT¹⁹
Supar (soluble urokinase plasminogen activator receptor): Predicts mortality across various critical conditions²⁰
Mid-regional pro-adrenomedullin: Shows promise for sepsis severity assessment²¹

Artificial Intelligence Integration

Machine learning approaches combining multiple biomarkers with clinical data may improve diagnostic and prognostic accuracy beyond individual markers.

Conclusion

Biomarkers in critical care represent powerful tools that, when properly understood and applied, enhance clinical decision-making. Procalcitonin excels in bacterial infection identification and antibiotic stewardship. Troponin provides valuable prognostic information and identifies cardiac involvement in systemic disease. IL-6 offers real-time inflammatory assessment in specialized situations. Ferritin serves as a marker of severe inflammation and specific hyperferritinemia syndromes.

The key to successful biomarker utilization lies in understanding their biology, recognizing their limitations, and integrating results with comprehensive clinical assessment. As critical care evolves toward personalized medicine, these biomarkers—used judiciously and interpreted correctly—will continue to play important roles in optimizing patient care.

The future likely holds more sophisticated biomarker panels, point-of-care testing, and AI-assisted interpretation. However, the fundamental principle remains unchanged: biomarkers are tools that enhance, not replace, clinical expertise and bedside assessment.

Key Clinical Takeaways

Use biomarkers to answer specific clinical questions, not as screening tests
Understand the timing: when markers rise, peak, and fall matters
Context is everything: patient population and clinical setting affect interpretation
Trends trump single values for most applications
Combine biomarkers with clinical assessment for optimal decision-making
Recognize limitations: false positives and negatives are common
Consider cost-effectiveness in biomarker ordering decisions

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Monday, August 25, 2025