Phenotyping ARDS Beyond Berlin Criteria: Hyperinflammatory versus Hypoinflammatory Subtypes and the Path to Precision Medicine

Dr Neeraj Manikath , claude.ai

Abstract

Background: The Berlin criteria for acute respiratory distress syndrome (ARDS) have served as the foundation for diagnosis and clinical trial enrollment since 2012. However, mounting evidence suggests that ARDS represents a heterogeneous syndrome with distinct biological subtypes that may respond differently to therapeutic interventions.

Objective: This review examines the emerging paradigm of ARDS phenotyping, focusing on hyperinflammatory and hypoinflammatory subtypes, and discusses implications for precision ventilation and tailored therapies.

Methods: We conducted a comprehensive literature review of studies published between 2014-2024 examining ARDS phenotypes, biomarker-driven classification, and personalized therapeutic approaches.

Results: Two primary phenotypes have been consistently identified: a hyperinflammatory phenotype characterized by elevated inflammatory biomarkers, shock, metabolic acidosis, and higher mortality; and a hypoinflammatory phenotype with lower inflammatory burden and better outcomes. These phenotypes demonstrate differential responses to PEEP, fluid management, and pharmacological interventions.

Conclusions: ARDS phenotyping represents a paradigm shift toward precision medicine in critical care. Understanding these subtypes may optimize therapeutic strategies and improve patient outcomes through personalized approaches to mechanical ventilation and pharmacotherapy.

Keywords: ARDS, phenotypes, precision medicine, mechanical ventilation, biomarkers

Introduction

Acute respiratory distress syndrome (ARDS) affects approximately 200,000 patients annually in the United States, with mortality rates ranging from 35-45% despite advances in supportive care¹. The Berlin definition, established in 2012, refined ARDS classification based on the degree of hypoxemia (mild, moderate, severe) but maintained a "one-size-fits-all" approach to management². However, this syndrome encompasses diverse pathophysiological processes with varying inflammatory responses, lung mechanics, and treatment responsiveness³.

The recognition of ARDS heterogeneity has catalyzed research into biological phenotypes—distinct subgroups with shared molecular, physiological, or clinical characteristics that may predict therapeutic response⁴. This paradigm shift from syndrome-based to phenotype-based medicine mirrors successful approaches in oncology and represents the future of precision critical care.

Historical Context and Limitations of Current Approaches

The Berlin Definition: Strengths and Limitations

The Berlin criteria improved upon the American-European Consensus Conference definition by:

Eliminating the confusing term "acute lung injury"
Introducing severity stratification based on PaO₂/FiO₂ ratios
Requiring minimum PEEP levels for classification
Emphasizing timing within one week of clinical insult²

However, several limitations have become apparent:

Clinical heterogeneity: Patients with identical Berlin criteria may have vastly different inflammatory profiles and outcomes
Treatment response variability: Interventions showing no benefit in heterogeneous populations may benefit specific subgroups
Prognostic limitations: Berlin severity categories incompletely predict mortality and treatment response⁵

Failed Therapeutic Trials: A Consequence of Heterogeneity?

Multiple promising ARDS therapies have failed in randomized controlled trials, including:

Anti-inflammatory agents (methylprednisolone, ketoconazole)
Antioxidants (N-acetylcysteine, vitamin E)
Surfactant therapy
Inhaled nitric oxide⁶

Post-hoc analyses increasingly suggest that treatment failures may result from biological heterogeneity rather than ineffective therapies, highlighting the need for phenotype-guided treatment selection.

ARDS Phenotypes: The Hyperinflammatory-Hypoinflammatory Paradigm

Discovery and Validation

Calfee and colleagues first described two distinct ARDS phenotypes using latent class analysis of clinical and biological variables from multiple randomized controlled trials⁷. This seminal work identified:

Hyperinflammatory Phenotype (~30% of patients):

Elevated plasma inflammatory biomarkers (IL-6, IL-8, TNF-α, sTNFr1)
Higher rates of vasopressor use and shock
More severe metabolic acidosis
Increased prevalence of sepsis
Higher mortality (44% vs. 23%)
More organ failures

Hypoinflammatory Phenotype (~70% of patients):

Lower inflammatory biomarker levels
Less hemodynamic instability
Better acid-base status
Lower mortality
Fewer non-pulmonary organ failures

These findings have been validated across multiple cohorts, including pediatric populations, and remain stable over the first 72 hours of illness⁸⁻¹⁰.

Clinical Pearl 💎

The "24-Hour Window": Phenotype classification appears most reliable within the first 24 hours of ARDS onset. Delayed classification may be confounded by treatment effects and clinical evolution.

Biomarker-Based Classification

Core Biomarkers

The most consistently discriminatory biomarkers include:

Inflammatory Mediators:

Interleukin-6 (IL-6): Central mediator of acute-phase response; levels >100 pg/mL strongly suggest hyperinflammatory phenotype
Interleukin-8 (IL-8): Neutrophil chemoattractant; elevated in hyperinflammatory patients
Soluble TNF receptor-1 (sTNFr1): Reflects TNF-α pathway activation
Interleukin-1 receptor antagonist (IL-1RA): Anti-inflammatory mediator, paradoxically elevated in hyperinflammatory patients¹¹

Epithelial and Endothelial Injury Markers:

Surfactant protein-D (SP-D): Alveolar epithelial damage marker
Receptor for advanced glycation end-products (RAGE): Type I pneumocyte injury
Angiopoietin-2: Endothelial activation and barrier dysfunction
von Willebrand factor: Endothelial injury and coagulopathy¹²

Clinical Pearl 💎

Biomarker Accessibility: While research-grade biomarkers provide phenotype precision, clinically available markers (procalcitonin, C-reactive protein, lactate) can approximate phenotype classification when specialized assays are unavailable.

Physiological and Radiological Differences

Respiratory Mechanics

Hyperinflammatory Phenotype:

Lower respiratory system compliance
Higher driving pressures at equivalent tidal volumes
Increased dead space fraction
Greater ventilation-perfusion mismatch¹³

Hypoinflammatory Phenotype:

Relatively preserved lung compliance
Lower inflammatory burden in bronchoalveolar lavage
Less severe gas exchange impairment
Better recruitment potential¹⁴

Radiological Patterns

Emerging evidence suggests phenotype-specific radiological patterns:

Hyperinflammatory:

More extensive bilateral infiltrates
Higher radiographic severity scores
Increased consolidation patterns
Greater quantitative CT lung involvement¹⁵

Hypoinflammatory:

More focal, patchy infiltrates
Lower overall radiographic burden
Preserved lung architecture in non-affected regions

Clinical Hack 🔧

Bedside Phenotyping Algorithm:

High suspicion for hyperinflammatory: Sepsis + shock + metabolic acidosis + bilateral infiltrates
Moderate suspicion: Any 2-3 of above features
Low suspicion (hypoinflammatory): ARDS without systemic inflammatory features

Precision Ventilation Strategies

PEEP Optimization by Phenotype

Traditional PEEP selection has relied on oxygenation-based approaches, but phenotype-guided strategies may improve outcomes:

Hyperinflammatory Phenotype:

Higher PEEP strategy: May benefit from PEEP >12 cmH₂O
Driving pressure limitation: Target <15 cmH₂O due to reduced compliance
Recruitment potential: Higher likelihood of recruitable lung
Evidence: Post-hoc analysis of ALVEOLI trial showed mortality benefit with higher PEEP in hyperinflammatory patients¹⁶

Hypoinflammatory Phenotype:

Lower PEEP strategy: May benefit from conservative PEEP approach
Overdistension risk: Higher baseline compliance increases barotrauma risk
Recruitment limitation: Less recruitable lung tissue
Evidence: Higher PEEP associated with potential harm in this phenotype¹⁶

Tidal Volume and Driving Pressure

Universal Principles:

Tidal volume 6 mL/kg predicted body weight remains standard
Driving pressure <15 cmH₂O associated with better outcomes
Plateau pressure <30 cmH₂O unless exceptional circumstances

Phenotype-Specific Considerations:

Hyperinflammatory:

May tolerate slightly higher driving pressures due to inflammation-mediated lung injury
Consider aggressive recruitment maneuvers
Monitor for evolving compliance changes

Hypoinflammatory:

Strict adherence to low driving pressure targets
Avoid aggressive recruitment in well-aerated lungs
Consider lower PEEP with adequate oxygenation¹⁷

Clinical Pearl 💎

Dynamic Phenotype Assessment: Respiratory mechanics may evolve during illness. Daily assessment of compliance, driving pressure, and PEEP response can guide phenotype-appropriate ventilation adjustments.

Tailored Therapeutic Approaches

Fluid Management

Hyperinflammatory Phenotype:

Conservative fluid strategy: Benefits from restrictive fluid management
Diuretic use: Earlier implementation may reduce lung water
Hemodynamic support: May require higher vasopressor support
Evidence: FACTT trial post-hoc analysis showed greater benefit from conservative fluid strategy¹⁸

Hypoinflammatory Phenotype:

Individualized approach: Less clear benefit from fluid restriction
Hemodynamic optimization: Focus on adequate perfusion pressure
Careful monitoring: Avoid excessive fluid restriction causing organ hypoperfusion

Pharmacological Interventions

Corticosteroids:

Hyperinflammatory: May benefit from anti-inflammatory therapy
Dosing: Methylprednisolone 1-2 mg/kg/day in divided doses
Duration: 7-14 days with gradual taper
Hypoinflammatory: Potential harm from immune suppression
Evidence: COVID-19 data supports phenotype-specific corticosteroid response¹⁹

Neuromuscular Blockade:

Hyperinflammatory: Greater benefit from early paralysis (first 48 hours)
Mechanism: Reduced ventilator-induced lung injury and metabolic demand
Hypoinflammatory: Less clear benefit; consider individualized approach²⁰

Prone Positioning:

Universal benefit: Recommended for severe ARDS regardless of phenotype
Hyperinflammatory: May show greater recruitment and mortality benefit
Implementation: ≥16 hours daily sessions for maximum effect²¹

Clinical Hack 🔧

Phenotype-Guided Treatment Protocol:

Immediate assessment: Biomarkers + clinical features within 24 hours
Hyperinflammatory: Higher PEEP + conservative fluids + consider steroids
Hypoinflammatory: Moderate PEEP + individualized fluids + avoid steroids
Reassess: Daily evaluation for phenotype evolution

Emerging Phenotyping Technologies

Machine Learning Approaches

Advantages:

Integration of multiple data types (clinical, laboratory, imaging)
Real-time phenotype prediction
Continuous phenotype monitoring
Identification of novel subtypes²²

Limitations:

Computational complexity
"Black box" decision-making
Validation requirements
Implementation barriers

Point-of-Care Biomarker Testing

Current Development:

Rapid IL-6 assays (results in <30 minutes)
Multiplexed inflammatory panels
Integration with electronic health records
Cost-effectiveness considerations²³

Imaging-Based Phenotyping

Quantitative CT Analysis:

Automated lung segmentation
Regional ventilation/perfusion assessment
Inflammation mapping
Longitudinal monitoring capabilities²⁴

Oyster Warning ⚠️

Technology Integration Challenges: While promising, these technologies require extensive validation before clinical implementation. Beware of over-reliance on algorithmic approaches without clinical correlation.

Clinical Implementation Strategies

Practical Phenotyping in Resource-Limited Settings

Simplified Classification:

Clinical variables: Sepsis, shock, acidosis, organ failures
Basic laboratory: Lactate, procalcitonin, CRP
Physiological: Compliance, oxygenation index
Radiological: Infiltrate severity and distribution

Implementation Framework:

Screening: All ARDS patients within 24 hours
Classification: Use available biomarkers and clinical features
Treatment allocation: Phenotype-appropriate ventilation and therapies
Monitoring: Daily reassessment for phenotype evolution

Quality Improvement Integration

Process Measures:

Time to phenotype classification
Adherence to phenotype-specific protocols
Biomarker turnaround times

Outcome Measures:

Ventilator-free days
ICU length of stay
Mortality at 28 and 90 days
Ventilator-induced lung injury markers²⁵

Clinical Pearl 💎

Implementation Pearls:

Start with simplified phenotyping using available resources
Build institutional expertise gradually
Focus on high-impact interventions (PEEP, fluids, steroids)
Develop standardized protocols and order sets

Future Directions and Research Priorities

Precision Medicine Trials

Current Studies:

PHARLAP: Phenotype-guided PEEP selection
PETAL-PREVENT: Biomarker-directed therapy prevention
PRECISE: Personalized therapy based on molecular phenotypes²⁶

Design Considerations:

Biomarker-stratified randomization
Adaptive trial designs
Real-time phenotype monitoring
Combination therapy approaches

Novel Therapeutic Targets

Hyperinflammatory Targets:

JAK-STAT pathway inhibitors
Complement cascade modulators
Specialized pro-resolving mediators
Mesenchymal stem cell therapy²⁷

Hypoinflammatory Targets:

Epithelial repair enhancers
Barrier function restoration
Anti-fibrotic agents
Regenerative therapies

Pediatric and Special Populations

Knowledge Gaps:

Phenotype stability in children
Pregnancy-related modifications
Immunocompromised hosts
Long-term outcome differences²⁸

Clinical Hack 🔧

Research Participation Strategy: Consider enrolling appropriate patients in phenotyping studies to advance the field while potentially benefiting from precision approaches.

Practical Pearls and Clinical Considerations

Diagnostic Pearls 💎

Early Recognition: Hyperinflammatory patients often present with sepsis-induced ARDS and multi-organ failure within hours of ICU admission
Temporal Stability: Phenotypes remain relatively stable over the first 72 hours, allowing for consistent treatment approaches
Biomarker Surrogates: In the absence of specialized biomarkers, elevated lactate (>2 mmol/L), procalcitonin (>2 ng/mL), and vasopressor requirement can suggest hyperinflammatory phenotype
Mechanical Markers: Low compliance (<40 mL/cmH₂O) with high inflammatory markers strongly suggests hyperinflammatory phenotype

Management Pearls 💎

PEEP Titration: Use incremental PEEP trials (2-3 cmH₂O steps) with compliance monitoring to guide phenotype-appropriate strategies
Fluid Assessment: Daily fluid balance goals should consider phenotype: hyperinflammatory patients benefit from even-to-negative balance, while hypoinflammatory patients may tolerate neutral balance
Steroid Timing: If indicated, initiate corticosteroids within 72 hours of ARDS onset for maximum benefit in hyperinflammatory patients
Weaning Strategies: Hyperinflammatory patients may require longer mechanical ventilation but show greater improvement once inflammatory phase resolves

Oyster Warnings ⚠️

Phenotype Misclassification: Delayed recognition (>48 hours) increases risk of inappropriate treatment allocation
Dynamic Changes: Severe illness can cause phenotype evolution; reassessment is crucial
Overtreatment Risk: Aggressive interventions in hypoinflammatory patients may cause harm
Resource Allocation: Biomarker-guided care requires institutional commitment and resources

Controversies and Limitations

Ongoing Debates

Biomarker Thresholds:

Optimal cutoff values for phenotype classification
Single vs. multiple biomarker approaches
Cost-effectiveness of biomarker-guided care

Treatment Algorithms:

Degree of phenotype-specific modifications
Integration with existing protocols
Override criteria for clinical judgment

Outcome Prioritization:

Short-term vs. long-term benefit assessment
Quality of life considerations
Healthcare resource utilization²⁹

Study Limitations

Retrospective Analyses:

Most phenotyping evidence derives from post-hoc analyses
Selection bias in biomarker availability
Temporal relationship assumptions

Generalizability:

Limited diversity in study populations
Institutional practice variations
Healthcare system differences³⁰

Implementation Barriers

Technical Challenges:

Biomarker assay availability and cost
Integration with clinical workflows
Staff training requirements

Regulatory Considerations:

FDA approval for biomarker-guided algorithms
Clinical decision support integration
Liability and standard-of-care evolution

Recommendations and Clinical Guidelines

Immediate Implementation (Evidence-Based)

Phenotype Assessment: Evaluate all ARDS patients for hyperinflammatory vs. hypoinflammatory features within 24 hours
PEEP Strategy: Consider higher PEEP (>12 cmH₂O) in hyperinflammatory patients with adequate hemodynamics
Fluid Management: Implement conservative fluid strategy preferentially in hyperinflammatory patients
Corticosteroids: Consider methylprednisolone therapy in hyperinflammatory patients without contraindications

Recommended Implementation (Emerging Evidence)

Biomarker Integration: Incorporate available inflammatory biomarkers into clinical decision-making
Protocol Development: Create institutional phenotype-guided treatment algorithms
Quality Metrics: Track phenotype-specific outcomes and protocol adherence
Research Participation: Engage in phenotyping studies and clinical trials

Future Considerations (Investigational)

Point-of-Care Testing: Implement rapid biomarker assays when available
Machine Learning: Integrate algorithmic phenotyping tools as they become validated
Precision Therapeutics: Adopt novel phenotype-specific therapies as evidence emerges

Conclusion

The paradigm shift from syndrome-based to phenotype-based ARDS management represents one of the most significant advances in critical care medicine in decades. The identification of hyperinflammatory and hypoinflammatory subtypes provides a framework for precision medicine that may finally unlock the therapeutic potential that has remained elusive in this heterogeneous syndrome.

Current evidence supports the integration of phenotype assessment into routine ARDS care, particularly for PEEP selection, fluid management, and corticosteroid therapy. While challenges remain in biomarker accessibility and algorithm validation, the consistent findings across multiple cohorts and the growing body of mechanistic understanding provide confidence in this approach.

The future of ARDS management lies in the continued refinement of phenotyping strategies, development of point-of-care diagnostic tools, and the conduct of adequately powered precision medicine trials. As we move beyond the limitations of the Berlin criteria, we enter an era where the heterogeneity of ARDS becomes not a barrier to treatment, but a roadmap to personalized care.

For the practicing intensivist, the message is clear: ARDS is not a single disease but a syndrome of multiple distinct entities. Understanding these phenotypes and their therapeutic implications may be the key to improving outcomes in one of critical care's most challenging conditions.

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Conflicts of Interest: The authors declare no conflicts of interest relevant to this review.

Funding: nil

Acknowledgments: The authors thank the critical care community for advancing ARDS phenotyping research and the patients and families affected by ARDS who make this research possible.

Friday, September 19, 2025