What are the different phenotypes of sepsis and their corresponding treatment approaches?

Sepsis Phenotypes and Treatment Approaches

Machine learning analysis of routine clinical parameters has identified four distinct sepsis subphenotypes that demonstrate differential mortality and treatment responses, representing the most clinically actionable approach to sepsis phenotyping currently available. 1, 2

Understanding Sepsis Phenotyping Terminology

Before discussing specific phenotypes, it's critical to understand the hierarchy of classification:

• Phenotype: Sepsis itself is a clinically observable syndrome characterized by dysregulated host response to infection with organ dysfunction 1
• Subphenotype: Distinct subgroups within sepsis based on shared measurable properties that can be reliably discriminated from each other 1
• Endotype: Subphenotypes with distinct pathobiological mechanisms that may predict specific treatment responses 1
• Treatable trait: Clinical characteristics/biomarkers indicating underlying mechanisms that respond to specific interventions (e.g., hyperinflammation) 1

The Four Machine Learning-Derived Sepsis Subphenotypes

The most robust evidence comes from machine learning models analyzing >25 routinely measured clinical parameters in electronic health data, which consistently identify four distinct sepsis subphenotypes. 1, 2 These parameters include:

• Vital signs (temperature, heart rate, blood pressure, respiratory rate) 2
• Laboratory values (complete blood count, metabolic panel, lactate) 2
• Organ dysfunction scores (SOFA, APACHE) 2
• Demographic data universally available in standard care 2

This approach requires no specialized biomarkers and can be implemented globally, making it superior to biomarker-dependent classification systems. 2

Alternative Six-Subphenotype Classification

Latent class analysis of the PROWESS Shock trial (n=1,696) identified six clinically meaningful subphenotypes with excellent separation (entropy 0.92): 3

1. "Uncomplicated Septic Shock" - baseline septic shock without major complications 3
2. "Pneumonia with ARDS" - respiratory-predominant presentation 3
3. "Postoperative Abdominal" - surgical source with abdominal pathology 3
4. "Severe Septic Shock" - high severity scores and multi-organ involvement 3
5. "Pneumonia with ARDS and MODS" - respiratory failure with multiple organ dysfunction 3
6. "Late Septic Shock" - delayed presentation or recognition 3

However, this classification has not been as widely validated or implemented as the four-phenotype model. 3

Clinical Parameter-Based Approaches for Practical Use

For bedside application, validated 3-4 variable classifiers using readily available clinical data can reliably identify subphenotypes with differential mortality and treatment responses. 2 These include:

• Respiratory system compliance in ARDS patients: Identifies subgroups with differential response to low tidal volume ventilation 1, 2
• SOFA score: Quantifies organ dysfunction severity and serves as prognostic indicator 2
• Number of acquired organ system failures: The single most important prognostic indicator for ICU patients 2
• Ventilatory ratio: Estimates ventilatory efficiency and predicts benefit from extracorporeal CO2 removal 1

Treatment Implications by Subphenotype

Critical Caveat About Treatment Heterogeneity

Clinical severity criteria alone achieve prognostic enrichment but generally fail to enrich for treatment response. 1, 2 This explains why many sepsis trials targeting specific organ dysfunctions have failed:

• The SCARLET trial showed no survival benefit from thrombomodulin for sepsis-associated coagulopathy when treating all patients uniformly 1
• However, exploratory analysis identified treatment heterogeneity even within coagulopathy patients when classified into distinct clusters 1

Differential Treatment Responses Documented

Integration of clinical, biological, and physiologic data provides more robust subphenotyping than single modalities and reveals differential treatment effects: 2

• ARDS subphenotypes show divergent responses to PEEP strategies, fluid therapy, simvastatin, and activated protein C 1
• AKI subphenotypes in sepsis demonstrate different responses to vasopressin versus norepinephrine 1
• Respiratory compliance-based stratification identifies patients who benefit most from low tidal volume ventilation 1, 2

Immunologic Phenotypes (Emerging but Not Yet Clinically Actionable)

There is interest in immunologic phenotyping (e.g., monocyte HLA-DR for immunoparalysis), but defining reliable thresholds remains challenging in practice. 1 Future precision trials combining cellular, proteomic, and genomic expression are planned but not yet ready for clinical implementation. 1

Practical Algorithm for Phenotype-Guided Management

Step 1: Identify sepsis using standard criteria and initiate immediate treatment 4

• Administer broad-spectrum antibiotics within 1 hour 4
• Obtain blood cultures before antibiotics (if no delay >45 minutes) 4
• Begin fluid resuscitation targeting tissue perfusion 4

Step 2: Classify using readily available parameters 2

• Calculate SOFA score for severity stratification 2
• Document number and type of organ failures 2
• For mechanically ventilated patients: measure respiratory system compliance 1, 2
• Identify infection source (pneumonia, abdominal, urinary, etc.) 3

Step 3: Apply phenotype-specific considerations 1

• High respiratory compliance ARDS: May tolerate higher tidal volumes if needed 1
• Low respiratory compliance ARDS: Strict adherence to lung-protective ventilation critical 1
• Multiple organ failures: Consider more aggressive source control and broader antimicrobial coverage 2
• Postoperative abdominal sepsis: Early surgical re-evaluation essential 3

Step 4: Reassess daily for de-escalation 4

• Review antimicrobial regimen based on culture results 4
• Consider procalcitonin-guided antibiotic discontinuation (NOT escalation) 5
• Typical duration 7-10 days unless specific indications for longer therapy 4

Critical Pitfalls to Avoid

Never use biomarkers to escalate or intensify antibiotic therapy - procalcitonin and similar markers should only guide de-escalation, not escalation. 5 Escalation decisions must be based on clinical deterioration, inadequate source control, or resistant organisms on culture. 5

Do not delay antibiotics for phenotyping - the one-hour antibiotic target supersedes all classification considerations. 5, 4 Phenotyping informs subsequent management decisions, not initial resuscitation. 2

Recognize that sepsis mimics exist - careful attention to medical/family history and focused diagnostic testing can identify treatable diseases masquerading as typical sepsis. 6 Confirmation bias is common because sepsis is frequent. 6

Understand global implementation challenges - subphenotyping approaches must use readily measurable parameters with acceptable operating characteristics to allow worldwide implementation. 2 Biomarker-dependent systems are not feasible in resource-limited settings. 2