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Strategies of cytokine response under
septic shock
Natalia Zotova
Eugeny Gusev
Laboratory of the Immunology of Inflammation
Institute of Immunology and Physiology, UB RAS
Yekaterinburg, 2018
TOPICALITY• Sepsis incidence in Russia – data is not available.
Sepsis in USA1 750 000 cases per year,
215 000 – lethal outcomes, average cost - 22 100$ / year.
Septic Shock (SS) - from 7 to 9.7 cases per 100 admission at ICU2
• Lethal outcomes in septic patients - 20-50%, with SS - 23-81%
• Incidence rate - 10-15% per year
• Subjectivity of a diagnosis3
• Unclear pathobiology (Sepsis-3)1. Alejandro Suarez De La Rica, Fernando Gilsanz, Emilio Maseda. Epidemiologic trends of
sepsis in western countries . Ann Transl Med 2016;4(17):325
2. Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic shock: the
CUB-Rea Network. Am J Respir Crit Care Med 2003;168:165-72.
3. Diagnosing sepsis is subjective and highly variable: a survey of intensivists using case
vignettes. Rhee et al. Critical Care (2016) 20:89
Progress in Sepsis definitions
Sepsis-1 (1991), Sepsis-2 (2001), Sepsis-3 (2015)
1 Sepsis: infection + SIRS Severe
sepsis
2 SIRS+ add. criteria (PCT + CRP),
+ > 80 SIRS markers
Infection SIRS ShockMODS
Nidus of infection SOFA SS criteriaCriteria:
Septic
shock
Sepsis-3 (2015)
Infection SIRS ShockMODS
Nidus of infection
SOFA Shock criteria
Criteria
SEPSIS
Septic Shock
life-threatening organ dysfunction caused by a
dysregulated host response to infection
Sepsis-3 // JAMA. – 2016. – Т. 315. – № 8. – С. 801-810.
Severe sepsis
Markers of systemic inflammatory response
under sepsis1. Cytokines 30-40 names out of 200, including:
• chemokines NAP-3, MIP-2α, IL-8, RANTES, МСР-1…
• pro-inflammatory - TNF-α, IL-6, IL-12, IL-18, MIF…;
• «anti-inflammatory» - RAIL-1, IL-10, TGF-β…
2. Soluble forms of some adhesion receptors: endocan, Е-
selectine, VCAM-1 и ICAM-1;
3. Heat stroke proteins – HSP70, HSP10, HSP60;
4. Soluble parts of PRR – presepsin, sTREM-1;
5. Acute phase proteins of the liver CRP, LPB;
6. Other.
AIM
to characterize cytokine response in
septic shock under both acute and
protracted / sub-acute septic processes.
Patients (n=31)
SS under tertiary peritonitis,
long and sub-acute
process (SS-SAP) (n=17)
• more, than 14 days after
sepsis were diagnosed,
n=17, age – 50.2±5.6 yrs.
Lethal outcomes n=26
Methods
Septic shock (SS) under
acute process (SS-AP)
(n=14)
• on the 1st–2nd days after
admission at ICU, mean
age – 54.9±16.4 years
Methods
• Plasma samples by Immuno-
chemiluminescence assay with Immulite
(Siemens Medical Solutions) :-IL-6 - С-reactive protein (CRP)
-IL-8
-IL-10
-TNF-α• Statistical analysis- «Statistica 6.0»
- SPSS 15,0 for Windows
RESULTSCytokine levels in the studied groups
(differences are significant, U-test, p<0,005)
ПОШ ОСШ0
4000
8000
12000
16000
20000
10 -1
2 g/
ml Median
25%-75% Min-Max
IL-6
SS-SAP SS-APSS-SAP
*
ПОШ ОСШ0
400
800
1200
1600
2000
2400
10 -1
2 g
/ml
IL-8
SS-SAP SS-AP
*
ПОШ ОСШ0
100
200
300
10 -1
2 g/
ml
IL-10
SS-SAP SS-AP
*
ПОШ ОСШ0
400
800
1200
1600
2000
2400
10 -1
2 g/
ml
TNFa
SS-SAP SS-AP
*
RESULTS
CRP levels in the studied groupsCRP
SS-SAPSS-AP
0
20
40
60
80
mg/
ml
Median
25%-75%
Min-Max
Difference is not significant
Correlation between evaluated mediators
under two variants of the process
Weak 0,4<R<0,6 Average 0,6<R<0,8 Strong 0,8<R<1,0
Degree of correlation
IL-6 IL-8 IL-10 TNFα CRP
IL-6 -
IL-8 -
IL-10 -
TNFα -
CRP -
SS-SAP SS-SP
Frequency (%) distribution by Reactivity Level in the
groups
0
20
40
60
80
12
34
5
0
36,4
54,5
9,1
0,0
00,0
15,4
46,2
38,5
SS-SAP SS-AP
%
Integral Reactivity Level (RL) takes into account blood level of the IL-6,8,10; TNFα;
CRP.
To estimate intensity of Systemic Inflammatory Response = systemic realizing of
cytokines.
RL
Frequency (%) of lethal outcomes
in groups
SS – acute process, n=14
SS – sub-acute
process, n=17
CONCLUSION
1.There are two variants of cytokine response in
septic shock: hyperergic under acute process
and depressive under sub-acute process.
2.To evaluate the cytokine response,
simultaneous detection of several cytokines
with different biological activity is necessary.
Acknowledgement of my colleagues’
contribution
Eugeny Gusev – Laboratory Head
Maria Lazareva – Surgeon, Department of Surgery,
Sverdlovsk Regional Clinical Hospital No 1,
Yekaterinburg, Russian Federation
Thank you for your attention!
Welcome to Yekaterinburg
- Systemic alteration
- Generalized focus mechanisms (internal level)
- Loss of biological appropriateness
Differences between
Local and Systemic
Inflammation
Zotova NV, Chereshnev VA, Gusev EY (2016) Systemic Inflammation:
Methodological Approaches to Identification of the Common Pathological Process.
PLoS ONE 11(5): e0155138. doi:10.1371/journal.pone.0155138
Main cytokine producers
Systemic inflammation «Classical» inflammation
Vessel macrophages and
the second type
endotheliocytes
(m ~ 1,5 kg).
Lymphocytes and myeloid
cells of inflammatory
infiltration
(m ~ 1÷150 g).
The association of the systemic
inflammation with cell stress
Generalized proinflammatory stages of cell stress↓
Disorders of microcurculation↓
Shock
Hypoergic
(depressive) phase
(cell tolerance, lower
concentration of
cytokines)
Hyperergic phase(cell resistant to
alteration, high level of
cytokines response)
Dynamics of Systemic
Inflammation
SI phases ratio (%) under
two variants of processes under
septic shock
AcuteSepsis (n=14) Sub-Acute
Tertiary peritonitis (n=17)21,4
78,6
Phlogogenic stroke Depressive
94,1
5,9Hyperergic Depressive
Inflammation levels
Alteration
Internal level
External level
(SIR)
Mediators
Focus (local)
level
Organism level
Systemic
Inflammation
Circumstances of trauma memory,
correction of the following action
Neuro-endocrine system
Ag-memory, correction of an immune response
to consequent Ag-actionна
Lymphoid organs
Marrow Liver
Metabolic ergotropism
Fever
APRLeukocytosis,
thrombocytosis
Ig, T-l
Inflammation Focus
Afferent
innervation
Ag
Metabolites
Psychas
theniaSympathopathy
HPAA
The «external» programme and inflammation focus correlation
Chereshnev V.A., Gusev E.Yu. , 2006.
Key Mechanisms of the first (“internal”)
level of reactivity
Postcapillary venule
endotheliocytesIgGIgM
Complement Hemostasis System
Th
PAMP Mast cells
Basophils and
eosinophils
Macrophages and
neutrophils
Th1IgGTh2
IgE
PAMP
PAMP
DAMP
DAMP
Contradictions of SIRS-sepsis concept • Clinically: sepsis is a multi-syndrome of unstable
composition (DIC, ARDS, MODS etc.);
• SIRS Criteria are excluded from diagnostics, but SIRS
ideology remains as a pathological basis;
• Low specificity of SIRS criteria to critical states;
• Sepsis diagnostics comes to MODS, but not to the
assessment of processes, which are the underling
MODS and Shock.
• The sepsis pathogenesis and aseptic critical states are
top related