Immune Dysfunction Pathology in Critical Illness

Quick Answer

CICM Exam Focus

Key Points

---

Normal Immune Response Overview

Innate Immunity

The innate immune system provides immediate, non-specific defense and comprises:

Physical and Chemical Barriers

• Skin: Keratinized epithelium, low pH (4.5-5.5), antimicrobial peptides (defensins, cathelicidins)
• Respiratory tract: Mucociliary escalator, mucus, surfactant proteins (SP-A, SP-D), alveolar macrophages
• Gastrointestinal tract: Gastric acid, bile salts, Paneth cell defensins, colonization resistance from microbiota
• Genitourinary tract: Urinary flow, vaginal pH, Tamm-Horsfall protein (PMID: 22343560)

Pattern Recognition Receptors (PRRs)

PRRs recognize conserved microbial structures (PAMPs) and endogenous danger signals (DAMPs) (PMID: 11138006):

Toll-Like Receptors (TLRs):

TLR4/LPS Recognition Complex (PMID: 15184896):

1. LPS-binding protein (LBP) transfers LPS to CD14
2. CD14 transfers LPS to MD-2
3. MD-2/LPS complex activates TLR4
4. TLR4 signals via MyD88 (pro-inflammatory cytokines) and TRIF (type I interferons)

NOD-Like Receptors (NLRs):

• NOD1: Recognizes iE-DAP (Gram-negative), activates NF-κB
• NOD2: Recognizes MDP (all bacteria), activates NF-κB and autophagy
• NLRP3 inflammasome: Activated by ATP, crystals, toxins → caspase-1 → IL-1β, IL-18 (PMID: 25430545)

Cellular Components

Neutrophils (PMID: 24629025):

• 50-70% of circulating leukocytes, first responders to infection
• Functions: phagocytosis, oxidative burst (NADPH oxidase → ROS), degranulation, NETosis
• Short-lived: 6-10 hours in circulation, 1-4 days in tissues
• Granules: Primary (MPO, defensins, elastase), Secondary (lactoferrin, collagenase), Tertiary (gelatinase)

Macrophages (PMID: 24484020):

• Tissue-resident phagocytes: alveolar (lung), Kupffer (liver), microglia (CNS), osteoclasts (bone)
• Functions: phagocytosis, antigen presentation (MHC II), cytokine production
• Polarization: M1 (IFN-γ, LPS → pro-inflammatory) vs M2 (IL-4, IL-13 → anti-inflammatory, tissue repair)

Natural Killer (NK) Cells (PMID: 18425107):

• Innate lymphoid cells, 5-15% of peripheral blood lymphocytes
• Functions: kill virus-infected cells and tumor cells without prior sensitization
• Recognition: "Missing self" (MHC I loss) and stress ligands
• Cytokine production: IFN-γ, TNF-α

Complement System (PMID: 20011988):

Three activation pathways converging at C3 convertase:

Complement Functions:

• Opsonization: C3b coats pathogens for phagocytosis
• Chemotaxis: C3a, C5a attract neutrophils
• Lysis: Membrane attack complex (MAC: C5b-9) forms pores in pathogen membranes
• Inflammation: C3a, C5a (anaphylatoxins) cause mast cell degranulation, vasodilation

Adaptive Immunity

The adaptive immune system provides highly specific, memory-capable responses:

T Lymphocytes (PMID: 10837056)

T Cell Activation Requirements:

• Signal 1: TCR recognition of peptide-MHC complex
• Signal 2: Costimulation (CD28 on T cell binds B7.1/B7.2 on APC)
• Signal 3: Cytokine signaling for differentiation
• Absence of Signal 2 → T cell anergy (functional inactivation)

MHC Restriction:

• MHC Class I (all nucleated cells): Presents endogenous antigens (viral) → recognized by CD8+ cytotoxic T cells
• MHC Class II (APCs: dendritic cells, macrophages, B cells): Presents exogenous antigens → recognized by CD4+ helper T cells

CD4+ T Helper Subsets (PMID: 17960159):

CD8+ Cytotoxic T Cells:

• Kill virus-infected cells and tumor cells
• Mechanisms: perforin/granzyme pathway, Fas/FasL pathway
• Develop into memory cells for rapid secondary response

B Lymphocytes

B Cell Activation and Differentiation:

1. Antigen binding to BCR (surface immunoglobulin)
2. T-dependent antigens: require CD4+ T cell help (CD40-CD40L interaction)
3. Germinal center reaction: somatic hypermutation, class switching
4. Differentiation to plasma cells (antibody secretion) or memory B cells

Immunoglobulin Classes (PMID: 19494541):

---

SIRS and CARS: The Biphasic Response

Systemic Inflammatory Response Syndrome (SIRS)

Definition and Pathophysiology

SIRS represents the systemic activation of the innate immune system in response to infectious (sepsis) or non-infectious (trauma, burns, pancreatitis) stimuli (PMID: 1597163).

The Pro-inflammatory Cascade (PMID: 23135902):

1. Recognition Phase: PAMPs/DAMPs activate TLRs on innate immune cells
2. Amplification Phase: NF-κB activation → transcription of pro-inflammatory genes
3. Cytokine Release: TNF-α (30-90 min), IL-1β, IL-6 (hours)
4. Systemic Effects: Fever, tachycardia, vasodilation, capillary leak, coagulopathy

Key Pro-inflammatory Mediators:

SIRS Clinical Criteria (1992) (PMID: 1597163):

≥2 of the following:

• Temperature >38°C or <36°C
• Heart rate >90 bpm
• Respiratory rate >20/min or PaCO₂ <32 mmHg
• WBC >12,000/mm³ or <4,000/mm³ or >10% bands

Compensatory Anti-inflammatory Response Syndrome (CARS)

Definition and Timing

CARS represents the counter-regulatory anti-inflammatory response that develops to prevent excessive tissue damage from uncontrolled inflammation. Critically, CARS begins SIMULTANEOUSLY with SIRS, not sequentially (PMID: 23063820).

Key Anti-inflammatory Mediators:

The Mixed Antagonist Response Syndrome (MARS)

MARS describes the complex interplay where elements of both SIRS and CARS coexist, leading to:

• Ongoing inflammation driving organ dysfunction
• Concurrent immunosuppression preventing infection clearance
• Susceptibility to secondary infections despite elevated inflammatory markers

---

Immunoparalysis: Mechanisms and Manifestations

Definition

Immunoparalysis is a state of acquired, reversible immunosuppression that develops in critically ill patients, characterized by (PMID: 24336061):

1. Monocyte HLA-DR expression <30% or <8,000 antibodies/cell
2. Impaired ex vivo cytokine production (TNF-α <200 pg/mL to LPS stimulation)
3. Increased susceptibility to secondary nosocomial infections
4. Inability to clear primary infection

Epidemiology

• Occurs in 30-50% of sepsis survivors by day 3-5
• Develops after trauma, burns, major surgery, pancreatitis
• Associated with longer ICU stay, mechanical ventilation duration
• Predicts secondary infections with 85-90% sensitivity
• Contributes to >50% of late sepsis deaths (PMID: 27830908)

Monocyte/Macrophage Dysfunction

HLA-DR Downregulation (PMID: 26845143)

Normal Function of HLA-DR:

• MHC class II molecule expressed on antigen-presenting cells
• Essential for presenting exogenous antigens to CD4+ T cells
• Required for adaptive immune response initiation

Mechanisms of Downregulation:

1. Cytokine-mediated:

   • IL-10 suppresses HLA-DR transcription
   • TGF-β inhibits antigen presentation
   • Glucocorticoids (endogenous and exogenous) reduce HLA-DR expression

2. Receptor internalization:

   • Persistent TLR activation leads to receptor desensitization
   • Internalization without recycling

3. Epigenetic modification:

   • Chromatin remodeling reduces CIITA (Class II transactivator) expression
   • Histone deacetylation at HLA-DR promoter

4. ER stress:

   • Sepsis-induced endoplasmic reticulum stress impairs protein folding
   • Reduced HLA-DR surface expression

Clinical Significance:

• mHLA-DR <30% or <8,000 Ab/cell is the gold standard for immunoparalysis
• Persistent low mHLA-DR (>48 hours) predicts secondary infection (OR 7.6)
• Threshold for considering immunostimulation: mHLA-DR <8,000 Ab/cell

Impaired Cytokine Production

Ex Vivo LPS Stimulation Test (PMID: 20196842):

• Whole blood incubated with LPS for 4-24 hours
• TNF-α production measured by ELISA
• Normal: >500 pg/mL; Immunoparalysis: <200 pg/mL
• Reflects monocyte functional capacity

"Monocyte Stunning":

• Despite normal or elevated monocyte counts
• Reduced phagocytic capacity
• Impaired respiratory burst
• Decreased antigen presentation
• Reduced chemokine production

Lymphocyte Apoptosis

Magnitude of Lymphocyte Loss (PMID: 11742046)

Sepsis induces profound lymphocyte depletion through apoptosis:

Apoptotic Pathways in Sepsis

Extrinsic (Death Receptor) Pathway (PMID: 12015787):

1. Death ligands (FasL, TRAIL, TNF-α) bind death receptors (Fas, DR4/5, TNFR1)
2. FADD adaptor recruitment
3. Caspase-8 activation
4. Caspase-3 activation → apoptosis
5. Elevated in sepsis: increased Fas/FasL on lymphocytes

Intrinsic (Mitochondrial) Pathway:

1. Cellular stress, DNA damage, cytokine deprivation
2. BH3-only proteins (Bim, Bad, Bid) activated
3. Bax/Bak oligomerization in outer mitochondrial membrane
4. Cytochrome c release
5. Apoptosome formation (cytochrome c + Apaf-1 + caspase-9)
6. Caspase-3 activation → apoptosis
7. In sepsis: Bim upregulation, Bcl-2 downregulation

Autopsy Evidence:

• Splenic white pulp depletion
• Lymph node follicular atrophy
• Abundant apoptotic bodies
• The spleen becomes an "immunological graveyard" (PMID: 10544155)

Absolute Lymphocyte Count (ALC)

ALC is a simple, widely available biomarker (PMID: 28490588):

• Normal: 1,500-4,000/μL
• Lymphopenia in sepsis: often <1,000/μL
• Severe lymphopenia: <500/μL
• Persistent lymphopenia (>day 4): 4-fold increase in mortality
• CD4 <200/μL: AIDS-like susceptibility to opportunistic infections

T-Cell Exhaustion

Definition and Phenotype (PMID: 22187279)

T-cell exhaustion is a state of T-cell dysfunction characterized by:

1. Upregulation of inhibitory checkpoint molecules:

   • PD-1 (Programmed Cell Death Protein 1)
   • CTLA-4 (Cytotoxic T-Lymphocyte Associated Protein 4)
   • LAG-3 (Lymphocyte Activation Gene 3)
   • TIM-3 (T-cell Immunoglobulin and Mucin-domain containing-3)
   • BTLA (B and T Lymphocyte Attenuator)

2. Functional deficits:

   • Reduced IFN-γ, IL-2, TNF-α production
   • Impaired proliferation
   • Decreased cytotoxicity
   • Reduced polyfunctionality (ability to produce multiple cytokines)

3. Transcriptional changes:

   • Altered transcription factor expression (T-bet, Eomes)
   • Epigenetic modifications distinct from naive or memory T cells

PD-1/PD-L1 Axis (PMID: 31039548)

Normal Function:

• PD-1 on T cells binds PD-L1/PD-L2 on APCs and tissue cells
• Provides inhibitory signal to prevent autoimmunity
• Essential for immune homeostasis

In Sepsis:

• PD-1 expression increased 2-4 fold on CD4+ and CD8+ T cells
• PD-L1 increased on monocytes and endothelium
• Correlates with lymphopenia and nosocomial infections
• Predicts mortality independent of severity scores

Therapeutic Implications:

• Anti-PD-1/PD-L1 antibodies (nivolumab, pembrolizumab) may reverse exhaustion
• Extensively studied in cancer immunotherapy
• Early phase trials in sepsis (PMID: 30870122)

Other Inhibitory Receptors

Neutrophil Dysfunction

Quantitative Changes (PMID: 26538105)

Despite often elevated neutrophil counts (neutrophilia), septic neutrophils are dysfunctional:

Neutrophilia Mechanisms:

• G-CSF release → bone marrow mobilization
• Demargination from endothelium
• Release of immature forms (bands, metamyelocytes)
• Delayed apoptosis → prolonged survival

"Left Shift":

• 10% band forms in peripheral blood

• Indicates bone marrow stress
• Immature neutrophils have reduced function

Functional Deficits

1. Impaired Chemotaxis (PMID: 15016617):

• Reduced directed migration toward infection
• Mechanisms: desensitization of chemokine receptors (CXCR1/CXCR2), reduced L-selectin (CD62L)
• Consequence: failure to localize to infection site

2. Reduced Oxidative Burst:

• Impaired NADPH oxidase assembly and function
• Reduced superoxide, hydrogen peroxide, hypochlorous acid production
• Consequences: impaired bacterial killing

3. Decreased Phagocytosis:

• Reduced Fc receptor and complement receptor expression
• Impaired actin cytoskeleton reorganization
• Reduced phagosome formation

4. Abnormal NETosis (PMID: 15001782):

• Initial hyper-NETosis may contribute to coagulopathy and organ damage
• Later: reduced NET formation contributes to impaired bacterial trapping
• Histone release causes endothelial damage

5. Delayed Apoptosis:

• Paradoxically prolonged neutrophil survival
• Leads to neutrophil tissue accumulation and damage
• Apoptotic neutrophils normally removed by macrophages → reduced efferocytosis

Myeloid-Derived Suppressor Cells (MDSCs) (PMID: 21890842)

MDSCs are immature myeloid cells with immunosuppressive function:

Characteristics:

• Phenotype: CD11b+CD14−CD15+ (granulocytic) or CD11b+CD14+HLA-DR−/low (monocytic)
• Expanded in sepsis, trauma, burns, cancer
• Arise from emergency myelopoiesis

Mechanisms of Suppression:

• Arginase-1: depletes L-arginine → T-cell anergy
• iNOS: produces NO → T-cell apoptosis
• ROS: damage T-cell receptors
• IL-10 and TGF-β production
• Direct T-cell suppression

Clinical Impact:

• Associated with secondary infections
• Predict poor outcomes
• Potential therapeutic target

---

Nosocomial Infections and Immune Status

Epidemiology of Secondary Infections (PMID: 27830908)

Secondary infections are a major cause of morbidity and mortality in ICU patients:

Risk Factors for Secondary Infection

Host Factors:

• Immunoparalysis (mHLA-DR <30%)
• Lymphopenia (ALC <1,000/μL)
• Age extremes
• Diabetes mellitus
• Chronic kidney disease
• Malignancy
• Malnutrition

ICU-Related Factors:

• Prolonged mechanical ventilation
• Central venous catheters
• Urinary catheters
• Total parenteral nutrition
• Broad-spectrum antibiotics (dysbiosis)
• Corticosteroid use
• Renal replacement therapy

Viral Reactivation (PMID: 28187750)

Latent viruses reactivate during immunoparalysis:

CMV (Cytomegalovirus):

• Reactivation in 20-35% of prolonged ICU stay
• Associated with prolonged ventilation, mortality
• Detection: CMV PCR in blood
• Consider treatment in severe cases (ganciclovir/valganciclovir)

HSV (Herpes Simplex Virus):

• HSV-1 reactivation common (oral, respiratory tract)
• HSV bronchopneumonitis in ventilated patients
• Detection: HSV PCR in respiratory samples
• Treatment: acyclovir

EBV (Epstein-Barr Virus):

• Subclinical reactivation common
• May contribute to lymphoproliferative disorders
• Usually monitoring only

The Microbiome and Colonization Resistance (PMID: 22688618)

Normal Function:

• Gut microbiota provides "colonization resistance" against pathogens
• Compete for nutrients and attachment sites
• Produce antimicrobial substances (bacteriocins)
• Stimulate mucosal immunity

Dysbiosis in Critical Illness:

• Antibiotics deplete commensal bacteria
• Overgrowth of pathogenic organisms
• Loss of Bacteroidetes and Firmicutes
• Expansion of Proteobacteria (Enterobacteriaceae)
• Contributes to C. difficile infection risk

---

Biomarkers of Immune Function

Clinical Biomarkers for Immunoparalysis (PMID: 30661131)

mHLA-DR Measurement (PMID: 26845143)

Methodology:

• Flow cytometry within 4 hours of blood draw (time-sensitive)
• Expressed as: % HLA-DR+ monocytes OR antibodies bound per cell (AB/c)
• Standardized kits available (Quantibrite system)

Interpretation:

• Normal: >15,000 Ab/cell or >90% HLA-DR+ monocytes
• Moderate immunosuppression: 8,000-15,000 Ab/cell
• Severe immunoparalysis: <8,000 Ab/cell or <30% HLA-DR+
• Trend more important than single value

Limitations:

• Requires specialized laboratory
• Sensitive to pre-analytical conditions
• Not widely available outside research settings

Novel and Emerging Biomarkers

Genetic/Transcriptomic:

• Sepsis Response Signature (SRS) endotypes (PMID: 27669021)
• SRS1: immunosuppressed phenotype, higher mortality
• SRS2: immunocompetent phenotype, lower mortality
• May guide personalized immunotherapy

Functional Assays:

• Neutrophil CD64 expression
• Monocyte CD163 expression
• Whole blood gene expression profiles
• Serum metabolomic profiles

---

Immunomodulatory Therapies

Rationale for Immunostimulation

Immunostimulatory therapy aims to reverse immunoparalysis and restore host defenses against secondary infections. Key principles (PMID: 31039548):

1. Patient selection: Only immunoparalyzed patients benefit; hyperinflamed patients may be harmed
2. Biomarker guidance: mHLA-DR <8,000 Ab/cell or ALC <1,000/μL
3. Timing: After initial resuscitation, during immunoparalysis phase (day 3-7+)
4. Monitoring: Serial biomarker assessment for response

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

Mechanism (PMID: 19643949):

• Stimulates myeloid cell production and function
• Upregulates HLA-DR expression on monocytes
• Enhances phagocytosis and oxidative burst
• Improves antigen presentation

Clinical Evidence:

Dosing: 4-8 μg/kg/day subcutaneously for 5-7 days

Adverse Effects:

• Fever
• Injection site reactions
• Splenomegaly (rare)
• Theoretical risk of exacerbating inflammation

IFN-γ (Interferon-gamma)

Mechanism (PMID: 12843657):

• Potent macrophage activator
• Upregulates HLA-DR expression
• Enhances antigen processing and presentation
• Induces Th1 polarization
• Activates antimicrobial mechanisms

Clinical Evidence:

Dosing: 100 μg subcutaneously daily for 7-14 days

Adverse Effects:

• Fever, chills
• Flu-like symptoms
• May worsen hyperinflammation if mistimed

IL-7 (Interleukin-7)

Mechanism (PMID: 29452037):

• Essential for T-cell survival and homeostatic proliferation
• Increases Bcl-2 (anti-apoptotic) expression
• Reverses lymphopenia
• Expands T-cell receptor repertoire
• Does NOT cause cytokine storm

Clinical Evidence:

Dosing: 3-30 μg/kg intramuscularly twice weekly

Advantages:

• Does not trigger cytokine release syndrome
• Specifically targets lymphopenia
• Expands diverse T-cell populations

Checkpoint Inhibitors (Anti-PD-1/PD-L1)

Mechanism (PMID: 30870122):

• Block inhibitory PD-1/PD-L1 interaction
• "Re-awaken" exhausted T cells
• Restore cytokine production and cytotoxicity
• Extensively used in oncology

Clinical Evidence:

• Phase 1b trials (PMID: 30870122): Safe in sepsis, reversed T-cell exhaustion
• Ongoing trials: Multiple Phase 2 studies

Candidates: Nivolumab, pembrolizumab (anti-PD-1); atezolizumab, durvalumab (anti-PD-L1)

Concerns:

• Immune-related adverse events (colitis, pneumonitis, hepatitis)
• May worsen hyperinflammation if mistimed
• Careful patient selection essential

Thymosin α1

Mechanism (PMID: 23689659):

• 28-amino acid thymic peptide
• Promotes T-cell differentiation and function
• Enhances dendritic cell maturation
• Used clinically in hepatitis B and as vaccine adjuvant

Clinical Evidence:

• Li et al. 2013: Reduced mortality in severe sepsis (Chinese study)
• Wu et al. 2013: Improved outcomes in sepsis (meta-analysis)
• Limited Western studies

Dosing: 1.6 mg subcutaneously twice weekly

Comparison of Immunomodulatory Agents

Precision Immunotherapy Approach

---

Australian/New Zealand Context

Epidemiology

• Sepsis is a leading cause of ICU admission in Australia (15-20% of admissions)
• ~18,000 sepsis hospitalizations per year in Australia
• ICU mortality for sepsis: 15-18% (ANZICS-CORE data)
• Indigenous Australians have 2-3× higher sepsis incidence and younger age at presentation

ANZICS-CORE Data

The Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation tracks:

• Sepsis-related ICU admissions and outcomes
• Implementation of sepsis bundles
• Benchmarking against APACHE/ANZROD predictions
• Quality improvement initiatives

Australian Clinical Care Standards

The ACSQHC Sepsis Clinical Care Standard (2022) emphasizes:

1. Early recognition
2. Antibiotics within 60 minutes
3. Blood cultures before antibiotics when feasible
4. Lactate measurement
5. Fluid resuscitation
6. Escalation of care
7. Documentation and communication

---

Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS)

Definition and Pathophysiology (PMID: 22809726)

PICS describes the phenotype of patients who survive the initial sepsis insult but develop chronic critical illness:

Key Features:

1. Persistent inflammation: Ongoing low-grade inflammation (elevated CRP, IL-6)
2. Immunosuppression: Chronically low mHLA-DR, persistent lymphopenia
3. Catabolism: Protein breakdown, negative nitrogen balance
4. Sarcopenia: Loss of muscle mass and function

Pathophysiology:

• Failed resolution of inflammation
• Inadequate counter-regulatory response
• Metabolic reprogramming toward catabolism
• Bone marrow exhaustion
• Chronic stress hormone elevation

Clinical Manifestations

• Prolonged ICU stay (>14 days)
• Persistent weakness and failed weaning
• Recurrent nosocomial infections
• Poor wound healing
• Cognitive impairment
• Cachexia
• High 1-year mortality (often 30-50%)

Management Principles

Supportive Care:

• Optimal nutrition (protein 1.2-2.0 g/kg/day)
• Early mobilization and rehabilitation
• Infection prevention bundles
• Minimize sedation
• Psychological support

Investigational Therapies:

• Immunonutrition (glutamine, omega-3)
• Anabolic agents (testosterone, oxandrolone)
• Growth hormone (controversial)
• Immunomodulation (GM-CSF, IL-7)

---

SAQ Practice Questions

---

Viva Scenarios

---

MCQ Practice Questions

---

---

References

Key Primary Literature

1. Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. Chest. 1992;101(6):1644-1655. PMID: 1597163

2. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. PMID: 26903338

3. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862-874. PMID: 24336061

4. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230-1251. PMID: 10446814

5. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol. 2001;166(11):6952-6963. PMID: 11359857

6. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci USA. 1999;96(25):14541-14546. PMID: 10588741

7. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594-2605. PMID: 22187279

8. Delano MJ, Ward PA. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev. 2016;274(1):330-353. PMID: 27830908

9. Venet F, Monneret G. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nat Rev Nephrol. 2018;14(2):121-137. PMID: 29276176

10. Monneret G, Venet F, Pachot A, Lepape A. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Mol Med. 2008;14(1-2):64-78. PMID: 18026570

HLA-DR and Biomarkers

11. Monneret G, Lepape A, Voirin N, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32(8):1175-1183. PMID: 16741700

12. Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36(11):1859-1866. PMID: 20652685

13. Docke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3(6):678-681. PMID: 9176497

14. Lukaszewicz AC, Grienay M, Resche-Rigon M, et al. Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med. 2009;37(10):2746-2752. PMID: 19707128

Immunomodulatory Therapies

15. Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180(7):640-648. PMID: 19643949

16. Nierhaus A, Montag B, Timmler N, et al. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med. 2003;29(4):646-651. PMID: 12649744

17. Döcke WD, Randow F, Syrbe U, et al. Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med. 1997;3(6):678-681. PMID: 9176497

18. Nierhaus A, Montag B, Timmler N, et al. Reversal of immunoparalysis by recombinant human granulocyte-macrophage colony-stimulating factor in patients with severe sepsis. Intensive Care Med. 2003;29(4):646-651. PMID: 12843657

19. Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3(5):e98960. PMID: 29452037

20. Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med. 2019;45(10):1360-1371. PMID: 31039548

21. Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand 1 antibody (BMS-936559). Crit Care Med. 2019;47(5):632-642. PMID: 30870122

T-Cell Exhaustion and Checkpoints

22. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15(8):486-499. PMID: 26205583

23. Chang K, Svabek C, Vazquez-Guillamet C, et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care. 2014;18(1):R3. PMID: 24387680

24. Guignant C, Lepape A, Huang X, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care. 2011;15(2):R99. PMID: 21418617

Neutrophil Dysfunction

25. Demaret J, Venet F, Friggeri A, et al. Marked alterations of neutrophil functions during sepsis-induced immunosuppression. J Leukoc Biol. 2015;98(6):1081-1090. PMID: 26538105

26. Brown KA, Brain SD, Pearson JD, et al. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368(9530):157-169. PMID: 16829300

27. Shen XF, Cao K, Jiang JP, et al. Neutrophil dysregulation during sepsis: an overview and update. J Cell Mol Med. 2017;21(9):1687-1697. PMID: 28244690

28. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004;303(5663):1532-1535. PMID: 15001782

MDSCs and Immunosuppression

29. Brudecki L, Ferguson DA, McCall CE, El Gazzar M. Myeloid-derived suppressor cells evolve during sepsis and are driven by serum S100A8/A9 proteins. J Immunol. 2012;189(6):2684-2691. PMID: 22889396

30. Cuenca AG, Delano MJ, Kelly-Scumpia KM, et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Mol Med. 2011;17(3-4):281-292. PMID: 21085745

31. Darcy CJ, Minigo G, Piera KA, et al. Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Crit Care. 2014;18(4):R163. PMID: 25084831

Secondary Infections and Viral Reactivation

32. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA. 2008;300(4):413-422. PMID: 18647984

33. Kalil AC, Florescu DF. Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med. 2009;37(8):2350-2358. PMID: 19531944

34. Walton AH, Muenzer JT, Rasche D, et al. Reactivation of multiple viruses in patients with sepsis. PLoS One. 2014;9(2):e98819. PMID: 24896293

35. Luyt CE, Combes A, Nieszkowska A, et al. Viral infections in the ICU. Curr Opin Crit Care. 2008;14(5):605-608. PMID: 18787457

PICS and Chronic Critical Illness

36. Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72(6):1491-1501. PMID: 22695414

37. Rosenthal MD, Moore FA. Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): a new phenotype of multiple organ failure. J Adv Nutr Hum Metab. 2015;1(1):e784. PMID: 25815387

38. Mira JC, Gentile LF, Mathias BJ, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med. 2017;45(2):253-262. PMID: 27632674

Innate Immunity and Pattern Recognition

39. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783-801. PMID: 16497588

40. Medzhitov R, Janeway CA Jr. Innate immunity: impact on the adaptive immune response. Curr Opin Immunol. 1997;9(1):4-9. PMID: 9039780

41. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282(5396):2085-2088. PMID: 9851930

42. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373-384. PMID: 20404851

Australian/NZ and Indigenous Health

43. Finfer S, Bellomo R, Lipman J, et al. Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med. 2004;30(4):589-596. PMID: 14991094

44. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311(13):1308-1316. PMID: 24638143

45. Thompson SC, Woods JA, Katzenellenbogen JM. The quality of Indigenous identification in administrative health data in Australia: insights from studies using data linkage. BMC Med Inform Decis Mak. 2012;12:133. PMID: 23157894

46. Greenland M, Knuiman M, Xiao J, et al. Cardiovascular mortality in Indigenous Western Australians: analysis using linked hospital and death records 1985-2015. Med J Aust. 2020;213(1):33-38. PMID: 32474935

Additional Key References

47. Rubio I, Osuchowski MF, Shankar-Hari M, et al. Current gaps in sepsis immunology: new opportunities for translational research. Lancet Infect Dis. 2019;19(12):e422-e436. PMID: 31036880

48. Venet F, Lukaszewicz AC, Payen D, et al. Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. Curr Opin Immunol. 2013;25(4):477-483. PMID: 23992989

49. Daix T, Guerin E, Tabone O, et al. Multicentric standardized flow cytometry routine assessment of patients with sepsis to predict clinical worsening. Chest. 2018;154(3):617-627. PMID: 29959928

50. Drewry AM, Samber N, Skrupky LP, et al. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42(5):383-391. PMID: 25051284

51. Hotchkiss RS, Opal S. Immunotherapy for sepsis--a new approach against an ancient foe. N Engl J Med. 2010;363(1):87-89. PMID: 20592301

52. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17(7):407-420. PMID: 28436424

---

Related Topics

• SIRS and Sepsis Pathology
• Immune System Physiology
• Sepsis Management
• Antimicrobial Pharmacology
• Shock Pathology
• Nosocomial Infections