WORKSHOP SEPSIS

JCCA

PATHOPHYSIOLOGY
OF SEPSIS
ANDI MUTYA PANGERANG, JULY 2022

Lewis Thomas (NEJM, 1972)

“The microorganisms that seem to have it in for us,
turn out to be rather more like bystanders. It is our
response to their presence that makes the disease.
Our arsenals for fighting off bacteria are so
powerful, that we are more in danger from them
than the invaders”

SEPSIS -3 DEFINITION

“LIFE-THREATENING ORGAN DYSFUNCTION

CAUSED BY DYSREGULATED HOST RESPONSE
TO INFECTION”
HOST RESPONSE
• Resistance of a host to pathogens and their toxic effects
• Immune system is human basic protection, their collective and coordinated response to
the introduction of foreign substance is called the immune response
• Role of immune system :
• Defense against microbes & growth of tumor cells
• Homeostasis : Destruction of abnormal or dead cells (e.g. dead red/white blood cells,
antigen-antibody complex)

NORMAL IMMUNE RESPONSE

• RECOGNIZING a potential harmful foreign antigen
• ACTIVATING and mobilizing forces of defense
• ATTACKING the harmful antigen
• CONTROLLING and ending the attack

IMMUNE SYSTEM
• ORGANS

• CELLS

• MOLLECULES

IMMUNE SYSTEM
1. ORGANS : - Primary Lymphoid organs → Thymus
Bone Marrow
- Secondary Lymphoid organs → Tonsils & adenoids
Lymph nodes
Lymphatic vessels
Spleen
Payer’s Patches
Appendix

IMMUNE SYSTEM
2. CELLS : - Lymphocytes → - T Lymphocytes
- B lymphocytes, plasma cells
- Natural killer lymphocytes
- Monocytes, macrophage
- Granulocytes → - Neutrophils
- Eosinophils
- Basophils

IMMUNE SYSTEM
3. MOLLECULES :

• Cytokines
• Antibodies
• Complements
• Interleukins
• Interferons

IMMUNE SYSTEM
1. INNATE IMMUNITY → Early Reaction
• First response of immune system
• Relies on mechanisms that exist before infection
2. ADAPTIVE IMMUNITY → Late Reaction
• Second line of response (if innate fails)
• Relies on mechanisms that adapt after infection

INNATE IMMUNITY
• Mechanical Barriers / Surface Secretions
Skin, cornea, acidic gastric PH, cilia, mucus layer, fatty acid on skin
• Cellular Defense Mechanism
Macrophage, natural killer cells, dendritic cells, basophils, eosinophils, neutrophils
• Humoral Mechanisms
Lysozymes, basic proteins, complements, interferons

Nature Reviews Cancer 2004 (4): 11-22

ADAPTIVE IMMUNITY
• CELL MEDIATED IMMUNE RESPONSE (CMIR)
- T-lymphocytes
- Eliminate intracellular microbes within phagocytes or other infected cells
• HUMORAL IMMUNE RESPONSE (HIR)
- B-lymphocytes, mediated by antibodies
- Eliminate extracellular microbes and their toxins

T CELLS (CMIR)
Mature in Thymus

Two Main Phenotype of • Responsible for

T cells : specific recognition of
antigen and can retain
CD4+ T cells (T helper) a ‘memory’ of antigen
CD8+ T cells (Cytotoxic • T cells goes into
T cells) effector cells stage
that is able to kill
infected cells

B CELLS (HIR)
Matured in Bone Marrow

• Produce specific
antibodies against
Can differentiate into invading organism
plasma cells (produce • Antibodies binds to
antibodies), and retain specific antigens on
‘memory’ of antigen microbes, destroy
microbes via specific
mechanism

Clin J Am Soc Nephrol , 2014. doi: 10.2215/CJN.04680514

Clin J Am Soc Nephrol , 2014. doi: 10.2215/CJN.04680514
 J In amm Res. 2018; 11: 477–502

INSULT

SYSTEMIC
INFLAMMATORY
RESPONSE

EXAGGERATED
IMMUNE
RESPONSE
fl
 SEPSIS

ORGAN DYSFUNCTION
 INFLAMMATORY RESPONSE :

• Message sent to nucleus → transmission of repressed genes

• Release of inflammatory mediators

• Normally protective

PLOS Medicine | DOI:10.1371/journal.pmed.1002022 May 17, 2016

• Dysregulated → SEPSIS

MECHANISM LEADING TO SEPSIS

J Pathol 2008; 214: 211–223

ORGAN INVOLVEMENT IN SEPSIS

• During sepsis, inflammatory

mediators found within
bloodstream can act on different
organs and induce tissue injury,
that will favor further production
of inflammatory mediators

• Cross talk between organs and

tissues is further mediated by
local mediators that can amplify
or limit the inflammatory
response

Mediators of In ammation 2016, Article ID 4062829

fl

ROLES OF INNATE AND ADAPTIVE IMMUNE RESPONSE IN SEPSIS PATHOPHYSIOLOGY

• Macrophage as first line defense, induce innate immune response

• Macrophage release :

• Pro-inflammatory cytokines (TNF⍺, IL-1ß,IL-6) that augment

systemic inflammation and epithelial barrier dysfunction

• Anti inflammatory cytokines (IL-10 & TGFß) to

counterbalance excessive immune response

• Chemokines (IL-8 & MCP-1) activate and promote neutrophil

migration toward inflammation site and to remote organs

• Systemic inflammatory mediators promote epithelial barrier

disruption to exaggerate inflammation and induce endothelial
ICAM-1 expression → binds to leukocyte and facilitate
transmigration of leukocytes across vascular endothelia

• Excessive neutrophil infiltration exaggerate inflammation and

organ injury by releasing other pro-inflammatory mediators
(MPO, NO, ROS, TNF⍺, IL-6)

J. Leukoc. Biol. 93: 329–342; 2013.

 • Immature DC + pathogen → Mature DC

(APC), activate adaptive immune system →
promoting T cells funtion
• Macrophage can also can also act as APC →
promote T cells activation and
differentiation
• Activated T cells differentiate into it’s
lineages, generating distinct cytokine
profile
• DC + pathogen can also trigger innate
immune functions by producing anti and
pro-inflammatory mediators
• In sepsis, immune cells undergo apoptosis
→ immunosuppression

J. Leukoc. Biol. 93: 329–342; 2013.

Critical Care Clinics 2020

Volume 36 Issue 2 Pages 391-399
 IMMUNE RESPONSE MODEL IN SEPSIS
CYTOKINE STORM
Innate Immunity 2019, Vol. 25(5) 267– 279
• Immune response in sepsis
transitions from hyper-
inflammatory to hypo-
inflammatory phase, followed by
resolution
• In hyper-inflammatory phase,
endotoxin responsive state with
cytokine storm is cytotoxic to
pathogen, immune and other organ
cells
• Endotoxin tolerance characterized
by down regulation of pro-
inflammatory cytokine and
chemokine expression, and up-
regulation of anti-inflammatory
IL-10 and TGF-ß expression

REAL LIFE IN THE ICU : DO OUR PATIENTS LOOK LIKE OUR MODEL OF SEPSIS?

Extremely high pro-inflammatory cytokine → Death • Individual response determined by many

factors ; virulence, size of inoculum,
Consider anti-inflammatory therapy
coexisting conditions, age, polymorphism in
genes for cytokines

• Initial response is hyper-inflammatory that

rapidly progress to hypo-inflammatory, a
secondary bump of hyperimmune state can
Anti-inflammatory therapy occur during hospital course with secondary
is likely harmful
infection
SEPSIS-INDUCED IMMUNOSUPPRESION

Hotchkiss RS, Karl IE, NEJM 2003. 348;2:138-150

 • The systemic reaction from

mediators spillover may have a
feature of an excess of either pro-
inflammatory or anti-inflammatory
response or a mixed pattern
• The clinical sequelae of sepsis may
vary depending on the balance of
the mediators

Am J Health-Syst PharmVol 59 Feb 15, 2002 Suppl 1

 TWO-PHASE MODEL OF SEPSIS-3

“Classical”

“Non-Classical”

SIRS : Systemic Inflammatory Response Syndrome

CARS : Compensatory Anti-inflammatory Response Syndrome

PICS : Persistent Inflammation, Immunosuppression and Catabolic Syndrome

Hindawi BioMed Research Int 2018, ID 5086516

Hindawi BioMed Research Int 2018, ID 5086516

CONCLUSION
• Normally, immune response are protective reaction to remove pathogen
• Spillover of pathogen and/or inflammatory mediators to systemic bloodstream followed by
exaggerated immune response leads to sepsis and organ dysfunction
• Excessive pro-inflammatory mediators together with endothelial and coagulation cascade
activation leads to vasodilatation, endothelial leakage, hypotension, microvascular thrombus and
reduced organ perfusion which can cause organ failure and death
• Classically, early response in sepsis is hyper-inflammation (SIRS) which rapidly progress to
immunosuppression (CARS). In clinical setting, CARS can be predominant or both can occur
simultaneously (MARS)
• If innate and adaptive immune system fails, inflammation and/or immunosuppression can persist
and become chronic (PICS), with high risk of secondary infection, re-admission and long term death

THANK YOU