Immunomodulator and Antioxidant

in Sepsis

Doni Priambodo Wijisaksono

Subdivision of Tropical Medicine and Infectious Disease
Internal Medicine Department
Dr. Sardjito General Hospital/Faculty of Medicine Gajah Mada University Yogyakarta
Indonesia
 Microorganisms represent
the first species of living organisms
that populated our planet
and will probably continue
to survive well
beyond the extinction
of the human race

(Fasano, 2002)
 DEFINITION

Immunomodulator:
Substance that affects the functioning of the immune
system

Antioxidants:
are compounds that inhibit oxidation. Oxidation is
a chemical reaction that can produce free radicals,
thereby leading to chain reactions that may damage the
cells of organisms
 DEFINITION


Sepsis, life-threatening organ dysfunction caused by
dysregulated host responses to infection

The clinical criteria, using the Sequential (Sepsis-
Related) Organ Failure Assessment (SOFA) score

qSOFA, positive if there are 2 of 3 criteria, and value
SOFA score more than 2
(Surviving Sepsis Campaign, 2016)
SOFA score
 Sepsis is a Significant Healthcare Burden

• Sepsis consumes significant healthcare resources

• In a study of Patients who contract nosocomial

infections, develop sepsis and survive:
• ICU stay prolonged an additional 8 days.
• Additional costs incurred were $40,890/ patient.

• Estimated annual healthcare costs

due to severe sepsis in U.S.
exceed $16 billion !!!
• Sepsis is a complex condition in which multiple
mediators are released, inducing a highly
multifaceted immunological and host tissue
response

• Recent data suggests that both the pro-

inflammatory and anti-inflammatory stages of the
host immune response to severe injury and/or
sepsis often occur simultaneously
The complexities of Pathophysiology
• Most of the unsuccessful therapies directed at
sepsis have focused on the pro-inflammatory
stage, and have not specifically addressed
sepsis-induced immune suppression

• Immunomodulatory agents or novel therapeutics

that enhance immune cell function are potentially
promising and should be investigated
Immunomodulator

-Immunorestoration :
Assisted immunomodulatory treatment :
Extracorporeal blood purification
Pharmacological methods :
IL-7, GM-CSF, IFN-γ, PD-1, PD-L1
CTLA-4 antagonists, IVIG, APC

- Immunostimulation :
isoprinosin, levamisol, echinacea, phyllantus sp,
centella aciata, morinda citrifolia, jamur maitake
- Immunosuppression
steroid, glutamine, purine antagonist
 Pathogenesis of sepsis:
Changes in the circulation during sepsis

Wong et al, Gut 2005;54;718-72

Consequently, there is increased anaerobic glycolysis in
cells resulting in the production of lactic acid. In addition,
the reactive oxygen species (ROS) produced by the
inflammatory response cause dysfunction of
mitochondria and a drop in ATP levels. These
mechanisms cause damage at the cellular level.
Sepsis Forum, Guntur, 2009
Antioxidants can be divided into three groups by
their mechanism:
(1) primary antioxidants, which function
essentially as free radical terminators
(scavengers);
(2) secondary antioxidants, which are important
preventive antioxidants that function by retarding
chain initiation; and
(3) tertiary antioxidants, which are concerned
with the repair of damaged biomolecules.
 ANTIOXIDANT AGENTS

1. Primary antioxidants, such as the enzyme

superoxide dismutase (SOD), catalase, and
glutathione dimustase.
2. Secondary antioxidants, such as vitamin E,
vitamin C, and β-carotene.
3. Tertiary antioxidants, such as enzyme that
repairs DNA in the cell nucleus, was methionine
sulfoxide reductase.
 • Is antioxidant therapy effective in sepsis ?

Oxidative stress has definite role on sepsis

Although some clinical and experimental studies have conflicting data, the
benefits of antioxidant treatment cannot be ignored and must be thought as a
supporting therapy

Tomruk,,Journal of Cellular Neuroscience & Oxidative Stress . 2018, Vol. 10 Issue 2, p680-681.

Selenium improves clinical outcome (infections, organ failure) and glutamine

reduces infectious complication in large-sized trials

Berger & Chiolero, Crit Care Med 2007, vol 35: S 58

 Several antioxidants such as vitamins C and E,
polyphenols, melatonin, β-glucan, N-
acetylcysteine, mitochondrion-targeted
antioxidants (MitoQ, MitoE, and peptides
associated with dimethyltyrosine), selenium salts,
and organoselenium compounds were effective in
ameliorating oxidative stress in animal models of
sepsis and in a number of clinical trials with septic
patients

Prauchner et al., Burn 2017, Vol 43: 471-485

Antioxidant protocol (Kehoe, 2017)
 Surviving Sepsis Campaign:
International Guidelines for Management
of Sepsis and Septic Shock: 2016

• Recommend against using Glutamine, IVIG,

Omega 3 (immunomodulator), and Arginine,
Selenium (antioxidant) in patients with septic and
septic shock

• Make no recommendation regarding the use of

blood purification techniques (immunomodulator)
 CONCLUSION


The role of immunomodulator and antioxidant in septic
patients is still controversial

In the future, certain immunomodulator and antioxidant
could be useful for treating sepsis, but it needs more
studies

SSC guidelines are intended to be best practice,
clinician should consider the recommendations
THANK YOU