Immunopathology of Sepsis and

Treatment Approach

Nur Farhanah
Divisision of Tropical Medicine and Infectious Diseases
FK UNDIP/KSM RSUP Dr Kariadi
 INTRODUCTION
• Sepsis with multiple organ dysfunction is the leading cause of mortality in
hospitalized patients.
• Approximately 31.5 million cases of sepsis, 19.4 million severe sepsis, and 5.3
million deaths reported annually.
• Sepsis-associated intensive care unit (ICU) mortality, is the most common cause of
death in ICU patients; severe sepsis accounts for >50% of ICU mortality.
• Patients with sepsis are also hospitalized longer and have an eight times higher risk
of death during hospitalization than other inpatients.
• Sepsis is a major public health challenge worldwide because of hyperinflammation,
immune suppression, susceptibility to secondary infections, and mortality

Cohen, J. et al.Lancet Infect. Dis. 15, 581–614 (2015).

Fleischmann, C. et al. Am. J. Respir. Crit. Care Med. 193, 259–272 (2016)
 Table 1. Definition of Sepsis

Older definitions Newer definition : Sepsis 3 (2016/2021)

Sepsis 1 (1992) Sepsis 2 (2001/2012) Definition

SIRS Screening for Sepsis : 1. Altered mental status

qSOFA (GCS ,15)
≥ 2 suspicion of sepsis and 2. SBP <100mmHg
organ dysfunction 3. RR>22/min

Sepsis : Sepsis : Sepsis Suspected or documented

documented /suspected infection + Documented or suspected infectionand some is life-threatening organ infection and an acute
≥ 2 SIRS criterias of the following: dysfunction caused by a increase of ≥2 SOFA
Parameters of General , hemodynamic, dysregulated host response to
Inflammatory, organ dysfunction ,Tissue infection
perfusion
Severe sepsis Severe Sepsis --------------------------
sepsis associated with organ Sepsis + organ dysfunction
dysfunction, hypoperfusion, or
hypotension
Septic shock Septic shock Septic shock Sepsis + vasopressor therapy
sepsis-induced with hypotension Sepsis + either hypotension or despite adequate fluid
despite adequate fluid resuscitation hyperlactatemian (need vasopressor, after resuscitation
adequate fluid resuscitation)
 • General parameters (fever, hypothermia,
HR>90bpm, tachypnea >30bpm, altered
mental status, edema/positive fluid balance,
hyperglycemia)
• Inflammatory parameters ( leukocytosis,
leukopeni,normal WBC with >10% immature
forms, CRP >2SD, PCT >2SD above n.v)
• Organ dysfunction parameters (arterial
hypoxemia, acute oliguria, Cr increase),
Coagulation abn, thrombocytopenia,
hyperbilirubinemia)
• Tissue perfusion parameters
(hyperlactatemia, decreased capillary refill)

Diaz G. https://www.grepmed.com/images/3223/septicshock-definitions-diagnosis-
criteria-sepsis
The evolution of sepsis definitions. SIRS,
systemic inflammatory response

Patel et al. CJASN 17: 880–889, 2022. doi:

https://doi.org/10.2215/CJN.14381121
Levy MM, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS
International Sepsis Definitions Conference. Crit Care
Med 2003;31:1250-6
Operationalization of Clinical
Criteria Identifying Patients with
Sepsis and Septic Shock

Singer M, et al. The Third International Consensus Definitions for

Sepsis and Septic Shock (Sepsis-3). JAMA 2016
SEPSIS-3
• SEPSIS 3 was defined as a life-threatening condition
of organ dysfunction caused by a dysregulated immune
response to infection.
• Two crucial elements in pathogenesis of sepsis:
1. The infection
2. The dysregulated host response
à management : eradication of the infection and
reconstitution of the dysregulated host response
• Focus of pathophysiology on sepsis-induced immune
dysfunction and long-term outcomes of sepsis patients
who survive from a fatal stage
• A large number of patients who died of sepsis had
unresolved secondary infections and
immunosuppressive features
Singer et al. JAMA. 2016;315:801–810
Kyriazopoulou E et al. Expert Opin Pharmaco
https://doi.org/10.1080/14656566.2019.1589451
Fig 1. Host Response in Sepsis

Angus DC. n engl j med 369;9 nejm.org august 29, 2013

Fig 2. Organ Failure in Sepsis

Angus DC. n engl j med 369;9 nejm.org august 29, 2013

Immunopathology of
Sepsis

Qi Yao R et al. Front Immunol. 2022; 13: 891024.

Cao et al. Cell Death and Disease (2019) 10:782
Cao et al. Cell Death and Disease (2019) 10:782
Immunopathology in sepsis

Bode C.et al Pharmacol Ther. 2020 Apr;208:107476. doi: 10.1016/j.pharmthera.2020.107476

• Sepsis is a critical illness with high mortality, but the initial features are
nonspecific and the diagnosis is based on nonspecific physiological criteria
(syndromic approach), which results in delayed diagnosis
• There is no ideal test to diagnose sepsis.
• Gold standard diagnosis of sepsis : presence of organism by blood culture (time
consuming, of culture under various situations)
àAlternative molecular-based methods such as enzyme-linked immunosorbent
assay kits, flow cytometry, immunoluminometric assays, PCR tests, automated
microbiological systems and fluorescence in situ hybridisation techniques
• Need various biomarkers and newer laboratory tests
• 180 biomarkers reported to be useful in sepsis
 Biomarker in Sepsis
‘an indicator of normal biological processes, pathogenic
processes or pharmacologic responses to a therapeutic
intervention
• Biomarkers can be used in suspected sepsis for :
1) identifying or ruling out sepsis
2) evaluating the severity and assessing the prognosis
3) evaluating patients’ response to proper treatment

An ideal biomarker should be validated, inexpensive and widely accessible, and

results should be rapidly available, high specificity and sensitivity, predictive value.
History of sepsis-biomarkers
 BIOMARKERS OF SEPSIS

Vassiliou AG, et al.Open Access book publisher Clinical Assays in Sepsis :

Prognosis , Diagnosis , Outcomes , and the Genetic Basis of Sepsis.
Classification of laboratorium tests based on
pathophysiological stages of sepsis
Biomarkers useful in management sepsis
Biomarkes useful in management sepsis
C-Reactive Protein
• an acute phase produced by liver in response to inflammation or tissue damage.
• Various cytokines induce its production (IL6)
• increase within 4–6 hours after the stimulus and doubles every 8 hours.
• half life is 19 hours and the peak level attained at 36–50 hours.
• cut-off value to diagnose infection is between 5 and 10 mg/dl.
• a sensitivity of 84.3%, specificity of 46.15%, positive-predictive value of 84% and negative-
predictive value of 42.8%.
• high negative-predictive value to exclude sepsis, if measured in the early course of illness.
• levels >100 mg/l are usually due to bacterial infection
 Procalcitonin
• In healthy individuals produced from
parafollicular cells of the thyroid and lung
and intestine.
• in patients with bacterial infection PCT is
produced from numerous organs
ü ≤0.15 ng/ml : normal reference value of
PCT
ü 0.15 and 2.0 ng/ml : localised infections
(without systemic signs) False negative :
ü people with localised infection
ü >2.0 ng/ml : systemic bacterial ü infection with atypical bacteria and in
infection/sepsis or severe localised bacterial ü patients on steroids.
infection. False positive : severe trauma, having surgery or after cardiac arrest
• persists as long as the infl ammatory
process continues ,correlates with the
severity of sepsis.
• produced in response to endotoxins or infl
ammatory mediators
 Procalcitonin

• the maximum level is reached by 6–8 hours and with continued

infection or sepsis the elevated level persists
• half-life is about 20–24 hours.
 Recommendation of Sepsis Treatment
• Understanding the pathophysiology of sepsis ,therapeutic
strategies must be complex and comphrehensive
• Sepsis treatment has recommended by SSC Guideline including :
à antibiotic therapies, resuscitative strategies,ventilator management,
blood glucose maintenance, and the supportive therapies, etc
Development of The clinical diagnosis
and treatment of sepsis
1. Screening and early treatment
2. Initial resuscitation
3. Mean arterial pressure
4. Admission to intensive care
5. Biomarkers
6. Diagnosis of Infection
7. Hemodynamic management
8. Ventilation
9. Additional therapies

Critical Care Medicine (DOI: https://doi.org/10.1097/ CCM.0000000000005337) and Intensive Care

Medicine (DOI: https://doi.org/10.1007/ s00134-021-06506-y).
Take Home Message
 Take Home Message
• Development of sepsis is characterized by systemic response is often biphasic, with an
early hyperinflammation with followed by immunosuppression.
• Biomarkers should be validated, inexpensive and widely accessible, and results should be
rapidly available, high specificity and sensitivity, predictive value
• Therapeutic strategies must be complex and comphrehensive due to pathophysiology of
sepsis
• Treatment strategies in sepsis, divided into standard-of care and adjunctive therapies
based on Sepsis Surviving Guideline
Thank you for attention