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