The Immunology of Sepsis: From Immunosuppression to Immunostimulation

A Review for Critical Care Postgraduates

Dr Neeraj Manikath , claude.ai

Introduction

Sepsis represents a dysregulated host response to infection, characterized by a complex and evolving immunological landscape. While the initial hyperinflammatory phase (often termed the "cytokine storm") has historically dominated our understanding, mounting evidence reveals that many sepsis patients transition into a prolonged state of immunosuppression—a phenomenon increasingly recognized as a key contributor to late mortality and secondary infections.(1,2) This paradigm shift has profound therapeutic implications, moving us from universal immunosuppression toward personalized immunomodulation.

The modern conceptualization of sepsis immunology recognizes two overlapping phases: an early pro-inflammatory state characterized by excessive cytokine release, complement activation, and neutrophil dysfunction, followed by a compensatory anti-inflammatory response syndrome (CARS) that may progress to persistent inflammation, immunosuppression, and catabolism syndrome (PICS).(3,4) This immunoparalyzed state is characterized by T-cell exhaustion, monocyte deactivation, increased regulatory T-cells, and impaired antigen presentation—leaving patients vulnerable to nosocomial infections and viral reactivations.(5)

Pearl #1: The temporal evolution of sepsis immunology is patient-specific; some patients exhibit profound early immunosuppression while others maintain hyperinflammation for weeks. Immunophenotyping, rather than time from diagnosis, should guide therapy.

Identifying the "Immunoparalyzed" Patient with Functional Assays

The critical challenge in sepsis immunotherapy lies in identifying which patients would benefit from immunostimulation versus continued immunosuppression. Traditional biomarkers like white blood cell counts and C-reactive protein provide limited insight into functional immune capacity. Several functional assays have emerged to characterize immune status:

Monocyte HLA-DR Expression (mHLA-DR)

Perhaps the most extensively studied marker, reduced mHLA-DR expression on monocytes (measured by flow cytometry) indicates impaired antigen presentation capacity. Multiple studies demonstrate that mHLA-DR levels <30% of normal (or <8,000-15,000 antibodies per cell) correlate with increased mortality and secondary infections.(6,7) The IMMUNOSEPSIS trial showed that persistently low mHLA-DR identified patients with impaired monocyte function and heightened infection risk.(8)

Technical Pearl: mHLA-DR measurement requires fresh blood samples and standardized flow cytometry protocols. The quantitative BRAI kit (Beckman Coulter) provides standardized measurements in molecules of equivalent soluble fluorochrome (MESF), improving reproducibility across centers.

Ex Vivo TNF-α Production Capacity

Whole blood or isolated monocytes stimulated with lipopolysaccharide (LPS) produce TNF-α, reflecting functional immune responsiveness. Reduced TNF-α production (<200 pg/mL after LPS stimulation) defines endotoxin tolerance and predicts poor outcomes.(9) This assay assesses the integrated function of pattern recognition receptors, intracellular signaling, and cytokine production machinery.

Hack: A simplified bedside test using TruCulture® tubes allows point-of-care assessment of TNF-α production capacity within 24 hours, though availability remains limited.

Neutrophil CD88 Expression

Neutrophil dysfunction in sepsis extends beyond mere quantitative abnormalities. Reduced CD88 (complement C5a receptor) expression indicates neutrophil exhaustion and impaired chemotaxis. Persistent CD88 downregulation identifies patients at risk for secondary infections and correlates with increased mortality.(10)

T-Cell Exhaustion Markers

Programmed death-1 (PD-1) and its ligand PD-L1 are upregulated on T-cells and monocytes during sepsis, contributing to T-cell anergy. Flow cytometric assessment of PD-1/PD-L1 expression, combined with evaluation of T-cell proliferative capacity using mixed lymphocyte reactions or anti-CD3/CD28 stimulation, provides insight into adaptive immunity dysfunction.(11)

Oyster #1: T-cell lymphopenia (<1,000 cells/μL) persisting beyond 48 hours is a powerful yet underutilized predictor of mortality in sepsis. This simple biomarker may identify patients warranting immune function assessment.

Integrated Approaches: SIRS and MARS

The Sepsis-related Organ Failure Assessment (SOFA) score guides general prognosis but provides no immune information. Emerging composite scores like the Multiple Organ Dysfunction Score with Immunological Variable (MODS-I) incorporate immune parameters. The Monocyte Distribution Width (MDW), recently FDA-cleared for sepsis detection, may also reflect immune dysregulation.(12)

Clinical Reality Check: Most functional assays remain research tools in 2025. Their implementation requires specialized laboratory infrastructure, standardized protocols, and clinical expertise. Until point-of-care tests become available, clinical phenotyping combined with surrogate markers (lymphocyte counts, secondary infections, viral reactivation) guides decision-making in most centers.

The Potential of Checkpoint Inhibitors and GM-CSF in Sepsis

The recognition of sepsis-induced immunosuppression has sparked interest in immunostimulatory therapies, particularly agents already used in oncology and hematology.

Checkpoint Inhibitors: Anti-PD-1/PD-L1 Therapy

The PD-1/PD-L1 axis serves as a critical immunological brake, preventing excessive T-cell activation but contributing to T-cell exhaustion in sepsis. Preclinical studies demonstrated that anti-PD-1 or anti-PD-L1 antibodies restore lymphocyte function, reduce bacterial burden, and improve survival in septic animals.(13)

The landmark phase 1b trial by Hotchkiss et al. (2019) evaluated nivolumab (anti-PD-1) in septic patients with persistent lymphopenia or reduced mHLA-DR expression. The trial demonstrated safety and promising signals of restored immune function, including increased mHLA-DR expression and enhanced ex vivo cytokine production.(14) However, the subsequent phase 2 trial (PETAL, expected completion 2024) has not yet reported definitive efficacy data.

Pearl #2: Patient selection is paramount. Checkpoint inhibitors administered during the hyperinflammatory phase could theoretically worsen outcomes. Target patients with documented immunoparalysis (low mHLA-DR, persistent lymphopenia, or secondary infections) presenting >72 hours post-diagnosis.

Safety Considerations: Unlike oncology patients who receive months of checkpoint inhibitor therapy, sepsis trials have used 1-3 doses. Immune-related adverse events (irAEs) appear less common with short courses, but clinicians must remain vigilant for autoimmune phenomena, cytokine release syndrome, and paradoxical hyperinflammation.(15)

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

GM-CSF represents an attractive immunostimulant based on its pleiotropic effects: monocyte/macrophage activation, neutrophil priming, enhanced phagocytosis, and restoration of mHLA-DR expression. Multiple phase 2 trials have evaluated GM-CSF (molgramostim or sargramostim) in sepsis.

A 2020 meta-analysis of randomized controlled trials showed that GM-CSF therapy increased mHLA-DR expression and reduced infection rates, with trends toward mortality reduction.(16) The largest trial to date, published by Meisel et al. (2009), demonstrated that GM-CSF administration to patients with low mHLA-DR (<8,000 antibodies/cell) significantly improved mHLA-DR expression, shortened mechanical ventilation duration, and reduced ICU length of stay, though mortality differences did not reach statistical significance.(17)

Oyster #2: A common misconception is that GM-CSF simply increases white blood cell counts. Its primary benefit in sepsis relates to functional immune restoration (enhanced antigen presentation, improved phagocytosis) rather than quantitative leukocytosis.

Practical Dosing: Most trials used 4-8 μg/kg/day subcutaneously for 5-8 days. Treatment initiation when mHLA-DR <8,000-15,000 antibodies/cell or clinical immunoparalysis is evident appears most logical, though optimal biomarker thresholds remain debated.

Interferon-Gamma (IFN-γ)

IFN-γ represents another candidate immunostimulant, primarily restoring monocyte function and mHLA-DR expression. A pilot trial in septic patients with reduced mHLA-DR demonstrated that adjunctive IFN-γ safely increased mHLA-DR and reduced infection rates.(18) However, larger confirmatory trials are lacking, and IFN-γ remains investigational.

Interleukin-7 (IL-7)

IL-7 combats T-cell apoptosis and exhaustion, representing a novel approach to adaptive immunity restoration. A phase 2 trial showed that recombinant IL-7 (CYT107) increased absolute lymphocyte counts and CD4+ T-cell populations in septic patients without significant adverse events.(19) Larger efficacy trials are ongoing.

Hack: While waiting for regulatory approval of novel immunostimulants, consider that intravenous immunoglobulin (IVIG), despite mixed evidence for mortality benefit, may provide passive immunological support in immunocompromised septic patients with documented hypogammaglobulinemia (<400 mg/dL).

Biomarkers to Guide Duration of Therapy and Risk of Secondary Infection

Precision medicine in sepsis requires biomarkers that not only diagnose immune dysfunction but also guide treatment duration and predict complications.

Predicting Secondary Infections

Secondary infections (ventilator-associated pneumonia, catheter-related bloodstream infections, urinary tract infections) complicate 25-40% of sepsis cases and substantially increase mortality. Several biomarkers predict this risk:

1. Persistent Lymphopenia: Absolute lymphocyte count <1,000 cells/μL beyond 48 hours identifies high-risk patients. Serial measurements improve prognostication; recovery of lymphocyte counts suggests immune reconstitution.(20)

2. Low mHLA-DR: Values <8,000 antibodies/cell persisting >3 days correlate strongly with secondary infections, including ICU-acquired infections and opportunistic pathogens.(7)

3. Viral Reactivation: Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) reactivation serve as functional indicators of T-cell immunosuppression. CMV viremia detected by PCR occurs in 15-35% of critically ill patients and associates with increased mortality.(21) While causality remains debated, reactivation reflects profound immunoparalysis.

Pearl #3: Don't dismiss viral PCR positivity as "colonization." In mechanically ventilated patients, HSV-positive bronchoalveolar lavage or CMV viremia may warrant antiviral therapy, especially when accompanied by end-organ manifestations or rising viral loads.

4. Presepsin and Soluble TREM-1: While primarily diagnostic markers, persistently elevated levels may indicate ongoing infection or immune dysregulation. However, their utility for predicting secondary infections requires validation.

Guiding Antimicrobial Duration

Traditional infection management relies on fixed-duration antibiotic courses (7-10 days for most infections). Biomarker-guided approaches may enable earlier cessation in recovering patients or extended therapy in immunocompromised hosts.

Procalcitonin (PCT): The most extensively studied biomarker for antibiotic stewardship, PCT-guided algorithms recommend continuing antibiotics when levels remain elevated or fail to decrease by >80% from peak, and stopping when levels normalize or substantially decline.(22) Meta-analyses demonstrate that PCT-guided strategies reduce antibiotic exposure without increasing mortality. However, PCT has limitations: false elevations with certain non-infectious conditions, reduced accuracy in renal failure, and inability to detect all infection types (particularly viral and fungal).

C-Reactive Protein (CRP): Less specific than PCT but widely available, CRP trends help assess treatment response. Failure of CRP to decline suggests treatment failure, resistant organisms, or undrained infection.

Oyster #3: Biomarkers should guide but not mandate decisions. A patient with resolving sepsis, normalizing PCT, but radiographic worsening of pneumonia should not have antibiotics discontinued. Clinical judgment remains paramount.

Immunological Biomarkers for Treatment Duration

The question extends beyond antibiotics: how long should immunomodulatory therapy continue?

mHLA-DR Recovery: In GM-CSF trials, treatment continued until mHLA-DR normalized (>15,000 antibodies/cell) or for a fixed 5-8 day course. Serial monitoring every 2-3 days allows response-guided therapy.(17)

Ex Vivo Functional Recovery: Restoration of TNF-α production capacity or improvement in lymphocyte proliferative responses indicates immune reconstitution and may guide immunostimulant discontinuation. However, these assays' complexity limits bedside applicability.

Clinical Recovery Markers: In the absence of sophisticated immune monitoring, clinical recovery (resolution of organ dysfunction, extubation, defervescence) combined with improving lymphocyte counts and infection biomarkers guides empiric immunotherapy duration.

Composite Risk Scores

Several scoring systems integrate multiple parameters:

APACHE-II and SOFA scores: While not immunology-specific, high scores (SOFA ≥6, APACHE-II ≥25) identify patients at greatest risk for complications warranting enhanced monitoring.

PERSIST Score (Predicting Enduring Sepsis and Immunosuppression): Incorporates age, chronic illness, organ dysfunction, and lymphocyte count to predict prolonged immunosuppression risk.(23)

Hack: In resource-limited settings without access to mHLA-DR or functional assays, use this practical approach: persistent lymphopenia (<1,000 cells/μL) + clinical immunoparalysis (new nosocomial infection after initial source control or viral reactivation) = candidate for immunostimulation.

Future Directions and Conclusion

The immunology of sepsis has evolved from a monolithic view of hyperinflammation to a nuanced understanding of temporal and patient-specific immune trajectories. The future of sepsis management lies in precision medicine: immunophenotyping patients in real-time, selecting appropriate immunomodulation (suppression vs. stimulation), and using biomarkers to guide treatment duration.

Key developments needed include:

Point-of-care immune function assays enabling rapid bedside immunophenotyping
Large randomized controlled trials of checkpoint inhibitors and GM-CSF in biomarker-selected populations
Validated composite biomarker panels integrating multiple immune parameters
Artificial intelligence approaches predicting individual patient trajectories and optimal therapies

Final Pearl: The "right" treatment depends on the "right" patient at the "right" time. Corticosteroids for hyperinflammatory COVID-19 pneumonia save lives; the same therapy might harm an immunoparalyzed patient with secondary Aspergillus infection. Develop institutional expertise in recognizing clinical immunosuppression even before sophisticated assays become available.

Until precision immunotherapy becomes standard, optimize fundamentals: early appropriate antibiotics, source control, judicious corticosteroid use, glycemic control, and nutritional support—the foundation upon which future immunomodulatory therapies will build.

References

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Disclosure Statement: The authors have no conflicts of interest to disclose.

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Thursday, November 6, 2025