9

Immunological Pathogenesis of Septic

Reactions and Elimination of Triggers
and Mediators of Inflammation
Irina Shubina, Natalia Anisimova, Elena Gromova,
Irina Chikileva and Mikhail Kiselevsky
NN Blokhin Russian Cancer Research Center
Russia

1. Introduction
Modern intensive therapy is armed with very sophisticated methods, however sepsis is still
one of the most challenging issues of medicine. Death rate in patients caused by sepsis
remains high and reaches about 30-80% (Yegenaga I. et al., 2004). This problem is especially
important in oncology, as every sixth septic patient has a diagnosis of cancer; and the death
risk of such patients is 30% higher (Angus D.C. et al., 2001).
The established bacteriologic paradigm of sepsis implies an infectious component for its
development. The priority in the pathogenesis of this disease has been assigned to
microorganisms, and therefore sepsis is regarded primarily as an infective disease.
However, over the last decades there have appeared tendencies for an essential revision in
the understanding of mechanisms of sepsis development; inflammatory reactions of the
organism are now regarded as important as infection. In particular, according to a current
definition, approved by American College of Chest Physicians/Society of Critical Care
Medicine (ACCP/SCCM) Consensus Conference, “sepsis is a systemic inflammatory
response syndrome developing in response to an invasion of different pathogenic
microorganisms, which is diagnosed if an infective agent and two or more signs of the
systemic inflammatory response are present” (USA, Chicago, 1991).
Systemic inflammatory response syndrome (SIRS) includes the whole set of the clinical
manifestations of systemic inflammatory response (SIR), which is a generalized form of
inflammatory reaction and is formed as a result of an excessive immune cell activation that
produce different types of mediators (cytokines, leukotrienes, thromboxanes, etc.). SIRS is a
necessary component of sepsis, however, it is not the same, as SIRS may be induced by
different non-infective causes such as trauma, pancreatitis, etc. Thus, signs of systemic
infection are necessary to prove diagnosed sepsis. Besides, it should be taken into account
that bacteremia is not pathognomonic to sepsis. The rate of diagnosed bacteremia even in
the most serious cases does not exceed 45% if accurate techniques of blood sampling and
modern microbiologic methods are applied. Detection of microorganisms in the patient’s
peripheral blood with no clinical and laboratory test conclusion of SIRS may be considered
as transitory bacteremia that is not necessarily caused by septic process. Some authors
158 Insight and Control of Infectious Disease in Global Scenario

recommend differentiating localized focus of infection from true sepsis even if it is

associated with the symptoms of systemic inflammatory reaction. In about half of cases (30-
60%) when clinical symptoms of sepsis were evident, it was impossible to isolate live
microorganisms from the blood or find the focus of infection.

Fig. 1. Triggering factors and mediators of sepsis.

The disease status that demonstrates the whole set of septic symptoms but lack of infection
is regarded like pseudosepsis or sepsis-like syndrome. Trigger factors initiating systemic
inflammatory response might be derivatives of microorganisms (exo- or endotoxins) rather
than microorganisms themselves, or even factors of non-infective origin including
endogeneous factors (such as tissue factors, elastin, thrombin, etc.), which appear primarily
during organ or tissue damage (Fig. 1) as a result of traumas, burns, etc.
Clinical symptoms of sepsis as well as organ or multi-organ dysfunction syndrome (MODS)
may develop in response to endo- and exotoxins of microorganisms in the absence of
bacteremia (septicemia) or localized focus of infection. The macroorganism reaction to
bacterial products displays totally the whole symptom complex that is characteristic for
bacterial sepsis. LPS poisoning does not only induce clinical presentations of sepsis and
septic (endotoxic shock), but leads to pathomorphologic changes characteristic for septic
conditions (Angus D.C. et al., 2001).
Present understanding of sepsis states that it is a systemic inflammatory response of the
macroorganism, which develops as a result of interaction of the immune system with
bacteria or their toxins and is mediated by the over-expression of a complex of humoral
factors: cytokines and other substances (platelet activation factor, metabolites of arachidonic
acid, endotelin-1, and complement components). Local tissue damage during SIRS arises
from the release of active oxygen forms, proteases and escalation of cytokine synthesis.
Such vision of sepsis pathogenesis suggests that new diagnostic and prognostic markers of
this condition should be identified in patient’s immunologic parameters. Following this
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 159

concept, new therapeutic strategies of inactivation or elimination of SIR triggers and

mediators are being developed.

2. Bacterial toxins: triggers of inflammation

Infective agents have various factors of virulence which can affect protective reactions of the
body. In septic and inflammatory conditions cascade of events initiated by microbes and
their products may develop out of control. Immune effectors recognize pathogens, firstly,
by innate immunity receptors detecting different pathogen-associated molecular patterns
that include various components of microbial cell wall (such as, LPS –lipopolysaccharide,
peptidoglycan, lipoteichoic acid, mannan, flagellin, bacterial DNA, viral double-helical
RNA, glucan and intracellular components, etc.)
Bacterial toxins, primarily LPS of gram-negative bacteria, have significant impact on
activating mechanisms of inflammation and may induce or potentiate systemic
inflammatory response in the absence of microbial cells. In particular, it was shown that in
humans LPS in the minimal dose (4 ng/kg) initiates release of inflammatory mediators,
alterations of hemostasis and fall of the blood pressure resulting from the decrease of the
cardiac output and vascular resistance. Sepsis-like conditions were described in volunteers
after injections of high endotoxin doses as well as in patients receiving therapies based on
LPS-immunomodulators (Laurenzi L. et al., 2004, Zucker T. et al., 2004). Sepsis-like
syndrome is observed in patients after cardiac surgery, closed injury, and in patients
resuscitated after cardiac arrest.
One of the major mechanisms of infection is penetration of normal microflora and
substances including endotoxins into blood circulation from the natural organism
biocoenoses, mainly from the bowels (Annane D. et al., 2005). Translocation of bacteria and
their toxins into the bloodstream might be caused by changes in the mucous intestine tunic
(Moore F.A. , 1999). Nevertheless, impairment of the intestine permeability most often has a
secondary origin and results from the SIR to trauma, surgical stress, burn, high-dose
antibiotic therapy and other damaging factors (Deitch E.A.&Bridges R.M. , 1987, Balzan S.et
al., 2007). In cancer patients, risk of bacterial toxin translocation increases due to disorders of
the intestine mucous barrier function caused by the major disease and especially, by anti-
tumor aggressive therapy. An additional unfavorable factor is older age of patients because
of the age-related changes in the intestines permeability. These patients, despite of the
widely accepted view about immunity involution and down-regulation of immune reactions
in the elderly, demonstrate an enhanced response to bacterial toxins. For example, patients
over 65 have a more significant drop of the blood pressure after injections of minimal LPS
doses (2 ng/kg) compared with younger individuals. The phenomenon is apparently linked
to the systemic chronic inflammatory reaction of the elderly, associated with a higher initial
level of pro-inflammatory factors.
When LPS enters blood circulation, it partly links to the LPS-binding protein (LBP) and the
newly formed complex interacts with CD14-positive cells, such as macrophages. LPB
potentiates LPS transport to receptors of macrophages (CD14) and stimulates functional
activity of these innate immunity effectors (Takeshita S. et al., 2002). The endotoxin-shipping
function in the blood also refers to the soluble circulating macrophage CD14-receptors. A
number of studies showed an increase in these markers in patients with sepsis, including
cancer patients (Myc A. et al., 1997, Nijhuis C. S. et al., 2003).
160 Insight and Control of Infectious Disease in Global Scenario

Our data show that LPS serum concentration increases in patients with sepsis aggravated by
organ failure or MODS. Particularly, in contrast to healthy volunteers, whose blood almost
lacks LPS, patients with kidney or hepatic failure with no symptoms of SIRS showed
moderate increase of LPS serum concentrations (0,1-0,2 IU/ml), while patients with sepsis
and septic shock had markedly increased blood serum concentrations of this bacterial toxin
– median parameter in the group was 0,55 IU/ml, sometimes reaching 6,25 IU/ml (Fig. 2).

Fig. 2. Comparative analysis of LPS serum level in groups of survival and died patients with
sepsis and in healthy volunteers.

A high LPS concentration in peripheral blood is generally associated with a drop of LPB
level. In patients with sepsis the ratio of blood serum concentrations LPS/LPB is on average
ten-fold higher than in healthy individuals. Therefore, dynamic growth of LPS concentration
and decrease of LPB level in sepsis may be considered as negative prognostic factors.

3. Cytokines
Over the last years, a lot of data have been accumulated that discuss the role of endogenic
bioregulators of different origin (cytokines, kinins, phospholipids, arachidonic acid
metabolites, etc.) in development of structural and functional alterations leading to systemic
inflammatory reactions and sepsis. Immune mediators – cytokines have an absolutely
important role in inflammation pathogenesis. Their high biologic activity and a small
difference between effective and toxic concentrations make them key factors both in natural
physiologic processes and pathologic conditions. As it was mentioned earlier, a triggering
mechanism of SIRS, besides bacteria and/or their toxins, might be a trauma, including
surgical intervention. With no microbial components it may also initiate an inflammatory
cascade, leading to cellular damage and organ dysfunctions. Different endogenous factors,
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 161

so-called alarmins, which are activated by tissue damage (for example, necrotic cells, RNA,
urine acid crystals, etc.), may bind leucocyte receptors and induce systemic inflammatory
response or “sepsis with no infective agent”. A term “alarmin” was suggested by J.
Oppenheim for endogenous stress molecules that provide signals about tissue and cell
damage (Oppenheim J.J.& Yang D., 2005).
Thus, excessive concentrations of these endogenous modulators provoke development of
pathophysiologic abnormalities leading to organ failure or MODS. However, despite
numerous studies looking at prognostic or diagnostic significance of cytokine concentrations
in the serum of patients with purulent and septic complications, there is still disagreement
on the topic. Serum cytokine low levels are registered in the peripheral blood of many
patients regardless clinical symptoms of sepsis or septic shock. At the same time, some
authors report data of increased concentrations of several cytokines such as interleukin(IL)-
8, tumor necrosis factor (TNF)α, IL-6 in the peripheral blood of patients with sepsis
(Calandra T.et al., 1990, Anderson R.&Schmidt R., 2010, Gaïni S. et al., 2006).
Risk of SIRS development is extremely high in cancer patients, as the necessary extensive
surgery stimulates release of pro-inflammatory cytokines that may promote development of
systemic inflammatory response (Hildebrand F. et al., 2005, Lenz A. et al., 2007). Some
authors suggested diagnostic and prognostic significance of TNF serum level (Calandra T.,
1990). The results showed both increased as well as similar to the control group
concentrations of TNF in serum of patients with severe sepsis. An unfavorable course of
the septic process was observed in the cases of low basic TNF level or its negative
dynamics (TNF level dropped from 30,4  2,7 pg/ml to 15,8  6,3 pg/ml). Originally high
TNF in the blood of septic patients (1020,7  30,1 pg/ml) was considered as a “cytokine
cascade out of control”. They also presented data demonstrating that intensive therapy in
the group of patients with originally high TNF concentration leaded to its significant
decrease (from 680,4  32,7 pg/ml to 450  16,7 pg/ml), which was associated with
favorable prognosis. TNF level varied in a wide range from 50 to 3500 pg/ml in patients
with septic shock. Median TNF level was 180 pg/ml in the group of survived patients; and
330 pg/ml in the group of the deceased. On the basis of these data, contradictory
conclusions were made about prognostic significance of pro-inflammatory cytokine serum
levels in general and TNF, in particular. However, many researchers agree that both high
and low TNF serum levels in critical conditions may be regarded as a poor prognostic
parameter (Martin C.et al., 1994, Quinn J.V.&Slotman G.J., 1999).
According to our data, only the concentration of IL-6 was significantly increased in the
peripheral blood of cancer patients with sepsis (Table 1). The highest mediator levels were
observed in patients with septic shock. A probable cause of the pro-inflammatory cytokine
increase in the patients’ blood could be its overproduction by the resident macrophages, in
particular, by the hepatic Kupffer cells. Besides TNF, IL-6 is one of the probable markers of
severity of an infective or non-infective stress. It induces production of a wide range of
proteins of the acute phase that regulate inflammation process. In septic shock, the cytokine
may directly affect organs and tissues; in particular, it may suppress myocardium. Various
studies investigated the role of this cytokine in pathogenesis of septic shock, MODS and
other systemic processes and its prognostic significance; however, their conclusions are
somewhat contradictory (Anderson R.&Schmidt R., 2010, Pinsky M.R., 2004).
162 Insight and Control of Infectious Disease in Global Scenario

Groups IL-6 IL-8 IL-10 INFγ TNFα TNF β IL-1β IL-4 IL-17
Cancer 203* 17 48 0 4 4 1 6 31
patients with
61÷494 6÷130 31÷163 0÷16 0÷30 4÷26 0÷28 3÷13 0÷73
sepsis
healthy 0 3 80 2 0 0 0 10 9
volunteers 0÷1 0÷11 0÷108 0÷16 0÷0 0÷9 0÷0 2÷12 6÷19
* − significant difference compared to the control group of healthy volunteers (P<0.01)
Table 1. Cytokine profile of cancer patients with sepsis compared to healthy volunteers
(median, 25th ÷75th quartiles), pg/ml.

On the whole, the above data suggest that determination of free cytokine serum
concentrations in the peripheral blood of patients with septic complications presents little
information, except for IL-6, which is statistically significantly increased in patients with
sepsis, and, especially, with septic shock. Therefore IL-6 is the only serum cytokine, which
concentration might be recommended as a marker for sepsis. A possible reason of low
importance of the cytokine profile determination in sepsis may be due to the fact that
commercially available kits are designed to evaluate concentrations of free (soluble)
cytokines only. It is a serious obstacle for the estimation of the total cytokine concentrations
secreted into the blood circulation. Even if free cytokines are not detected in the blood, their
receptor-bound complexes may be circulating. As a result, “hidden cytokinemia” – high
cytokine concentrations non-detectable by conventional methods – may take place.
Therefore, low levels of serum cytokines do not necessarily reflect the true mediator
concentrations in blood serum and may result not only from insufficient activity of immune
effectors of cancer patients, but also from specific binding with increased concentrations of
cytokine soluble receptors. A number of studies reported on the statistically significant
increase of concentrations of soluble cytokine receptors: TNF receptors (sTNF-R I and sTNF-
R II) (Zhang B.et al., 1998), IL-1 − sIL-1 RII (Müller B., 2002) and decrease of soluble IL-6
receptor (sIL-6 R) (Frieling J.T.M.et al., 1995, Zeni F. et al., 1995) in patients with sepsis.
However, other researchers presented different results (Barber M.D.et al, 1999).
The data of our studies showed that only sTNF-RI (р55) serum level was significantly more
enhanced in cancer patients with sepsis compared with control group of healthy volunteers.
However, the comparative analysis of cytokine and their soluble receptor concentrations in
the blood of survived and deceased patients with sepsis showed that simultaneous increase
of IL-6, IL-8, IL-10, sTNF-RI, sIL-1RII and sIL-6R was associated with poor prognosis.
Probably, the mentioned facts result from the so-called “cytokine storm” and reflect the
extreme imbalance of the immune system in sepsis leading to the fatal outcome. This
suggestion is supported by the increased level of both pro-inflammatory cytokines (IL-6, IL-
8) and anti-inflammatory IL-10 in the patients died from sepsis
Comparative studies of immunocompetent cell potential for cytokine secreting presented
more precise data. The level of spontaneous production of these endogenous bioregulators
characterizes the original physiologic activity of the blood cells. The intensity of the
stimulated cytokine production helps to determine the potential reactivity in response to a
possible infection.
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 163

The obtained data from our studies showed that blood cells of septic cancer patients with
spontaneous overproduction of certain cytokines (IL-6, IL-8) are mostly non-responsive to
any stimulation. The observation suggests that immune effectors in this group of patients
are over-stimulated.
The inflammatory reaction in response to trauma or infection is induced mainly by innate
immunity and develops rapidly at the early stage. Endogenous inflammation mediators
synthesized by immune cells in response to microbial components or tissue factors are
released within few minutes and may peak within 1-3 hours in peripheral blood. These
factors play a major role in the formation of the protective response to infection (they
enhance bactericidal activity of phagocytes, promote recruitment of leukocytes to the
infection site, stimulate hemopoiesis, and cause fever). However, inflammatory over-
reaction leads to an excessive release of inflammatory mediators both of peptide (cytokines)
and lipid nature (metabolites of membrane lipids –leukotrienes, thromboxanes, platelet
activation factor). These substances, besides protective functions, are highly toxic and may
cause hemodynamic imbalance, metabolic and pathologic alterations that are characteristic
for sepsis and septic shock. Activation of anti-inflammatory factors, as well as of inhibitors
of inflammatory mediators (prostaglandin E2, IL-1Ra, IL-10 and TGF-β), takes place during
SIRS and is considered as compensatory anti-inflammatory syndrome, a protective response
limiting tissue damage by endogenous pro-inflammatory factors. On the other hand,
prevalence of anti-inflammatory mediators may lead to immune suppression and anergy of
immune cells (Keel M.&Trentz O., 2005). Evidently, both hyper- and hypo-inflammatory
phases may follow each other or develop independently from each other, according to the
original reactivity of the organism. Both conditions of hyper- and hyporeactivity are equally
dangerous and may cause fatal outcome.

4. Functional activity of leukocytes

So far a lot of data have been collected to characterize immune status of cancer patients with
suppurative septic complications (Martin C., 1994, Quinn J.V.&Slotman G.J., 1999, Anderson
R.&Schmidt R., 2010, Pinsky M.R. et al., 2004, Zhang B. et al, 1998, Frieling J.T.M.et al., 1995).
Although most of the studies look at parameters of humoral immunity, particularly, at
assessment of cytokine profile, a higher interest has been seen in studying functions of
immune competent cells over the last years. Special attention is aimed at effectors of innate
immunity (natural killers, granulocytes and monocytes), which play a key role in
pathogenesis of sepsis (Zeerleder S., 2005). A number of authors show an increasing
suppression of cellular immunity with septic background that reveals as decreased function
of immune competent cells due to high rate of immunosuppressive agents (IL-10) and
decrease of regulatory peptides (IL-12). On the other hand, there are data that prove
enhanced production of pro-inflammatory cytokines (IL-8, TNFα, IL-6, IL-1β) in cancer
patients, which level is many times higher than that in healthy individuals (Rigato O.et
al., 1996, Kumar A.T. et al., 2009). The logic consequence of this phenomenon may be higher
cellular functioning, mostly - innate immunity effector cells function. In the environment of
bacteriemia and bacterial toxicity these cells are responsible for natural resistance to
infectious agents. However their super activation triggers cascade hyperproduction of
inflammatory mediators which initiate SIRS (Angus D.C. et al., 2001, Hildebrand F. et al.,
2005).
164 Insight and Control of Infectious Disease in Global Scenario

The results of our studies showed that cancer patients with sepsis have a significant increase
of natural killer (NK) cells activity as compared with cancer patients having no sepsis or
healthy volunteers. These data comply with results of other authors who demonstrated an
enhanced function of NK in patients with sepsis (Giamarellos-Bourboulis E.J.et al., 2006,
Yoneda O. et al., 2000). The observed phenomenon seemed to be associated with the
enhanced rate of IL-12 in blood serum of patients with severe sepsis or septic shock due to
the fact that IL-12 stimulates NK and T-killer cells cytotoxicity as a result of secreting
molecules involved in cytolytic reactions (gransymes A and B) (Zeerleder S., et al. 2005).
Neutrophils are the first line of protection against acute infections and play an important
role in pathogenesis of sepsis (Segal A.W. , 2005). On the one hand they are major players in
eliminating infectious microorganisms, on the other hand – an excessive release of oxidants
and proteases by neutrophils leads to damaging organs and tissues. Neutrophils are
involved both in inflammatory processes and natural immunity effects migrating to the site
of infection or inflammation to eliminate infectious agents. Besides that they produce signals
about invasion of a foreign agent to alert effectors of innate immunity. These signals induce
activation of other cells, such as, monocytes/ macrophages as well as epithelial and mast
cells and trombocytes. On activation neutrophils generate various chemotaxiс factors
attracting macrophages. Because of their common origin neutrophils and macrophages have
common functions (phagocytosis, similar behavioral kinetics in infectious and inflammatory
process, anti-microbial and immunomodulating functions). Activated neutrophils releasing
chemokines stimulate and recruit to the inflammation site monocytes and macrophages and
may effect on macrophage differentiation into pro- or anti-inflammatory subtype (type I or
type II macrophages). In addition to release of pro-inflammatory cytokines neutrophils also
secrete reactive oxygen radicals that induce acute tissue destruction, such as lung
destruction in acute reactive distress syndrome (ARDS) or pneumonia (Kumar V. et al.,
2010). Besides phagocytosis and secretion of anti-bacterial molecules neutrophils form so-
called extra-cellular traps. Extra-cellular traps are formed from the decondensated
chromatin and the contents of some granule, as well as from the cytoplasmic proteins and
can interact both with gram-negative and gram-positive bacteria leading to destruction of
virulent factors and killing bacteria. However the excessive reaction of innate immunity
following bacterial infection may lead to immune suppression in the end. Part of this
condition is impairment of neutrophil phagocytic activity, which is the major component
determining the status of anti-infectious defense (Kumar V. et al., 2010, Giamarellos-
Bourboulis E.J. et al., 2010, Volk H.D. et al., 1999).
Patients with sepsis and the background of neutrophil sequestration can often develop
complications in tissues, such as ARDS, and excessive activation of neutrophils is associated
with lung destruction (Kumar V. et al., 2010, Giamarellos-Bourboulis E.J. et al., 2010).
There is a number of data that demonstrate long-term cellular over-production of pro-
inflammatory cytokines (IL-8, TNFα, IL-6, IL-1β) in cancer patients with sepsis, which can
effect neutrophil functions (Martin C. et al., 1994, Zhang B. et al., 1998, Frieling J.T.M. et al.,
1995, Barber M.D. et al., 1999, Rigato O. et al., 1996, Segal A.W., 2005). The results revealed
that in most cases the phagocytotic activity of neutrophils of cancer patients with sepsis
(phagocytic index and phagocytic number) were higher than those of healthy volunteers (in
2,6 and 6,3 times, respectively) (Fig. 3a,b, Fig.4 a,b). This phenomenon may be the results of
increased production of pro-inflammatory cytokines, in particular IL-8: key cytokine
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 165

involved in recruitment of neutrophiles into the inflammation site and stimulating their
function (Hammond M.E. et al., 1995).

a Phagocytic index b Phagocytic number

*− values that have reliable difference from those of healthy volunteers (p<0,05).
Fig. 3. Parameters of phagocytosis rate of blood granulocytes in cancer patients with sepsis
and patients with no septic symptoms in comparison with healthy volunteers (median,
25%÷75%).

a b
Fig. 4. Microphotos of neutrophils in peripheral blood of healthy volunteers (а) and cancer
patient with sepsis (b ) after incubation with latex particles (t=40 min).

Patients with sepsis have a significant increase in activation of oxygen dependent

mechanisms of phagocytes as compared to those of patients with no complications or
healthy volunteers (5-fold and 15-fold, respectively) that points to a high rate of activation of
intracellular bactericidal systems when there is septic process (Fig. 5).
Hydrogen peroxide combined with myeloperoxidase (enzyme of primary neutrophil
granules) and halogen ions forms an effective bactericidal system that kills bacteria by
halogenation of the cellular wall (Zychlinsky A. et al., 2003). But phagocytes release these
endogenous active substances into the inter-cellular medium so that they also destroy self-
166 Insight and Control of Infectious Disease in Global Scenario

tissues and thus they become involved in developing organ dysfunction or MODS (Thomas
S. et al., 2004).
Previous studies suggest that the basis for MODS in critical conditions is the impairment of
vessel endothelium, which was the result of active function of immune competent cells
induced by microbial products. Therefore super-activation of effectors of innate immunity
(neutrophils, natural killers) may be considered as an important link in pathogenesis of
organ or multi-organ dysfunction syndrome.
Excessive reaction of innate immune system after contact with bacterial infection can lead to
immune suppression. A part of this condition is the disorder in phagocytic function of
neutrophils, which to a high extent determines anti-infectious defense (Volk H.D. et al.,
1999, Alves-Filho J.C. et al., 2010, Giamarellos-Bourboulis EJ et al., 2010).
One of the results of the developing immune suppression in patients with sepsis can be
decreased number of lymphocytes that is associated with their sequestration in the
inflammation site or their apoptotic death as a result of the excessive production of pro-
apoptotic factors. Clinical studies showed marked T-cell lymphopenia with its maximum
within a few days. Absolute and relative number of CD4+ and CD8+ T-lymphocytes
reduces. At the same time percentage of B-lymphocytes in the peripheral blood goes up
(Murphy R.&DeCoursey T. E., 2006, Holub M. et al., 2000). Essential alterations were
observed in NK examination (Emoto M. et al., 2002, Kerr A.R., et al., 2005).

*− values that have reliable difference from control (p<0,05);

**− results of the induced NB-test reliably different from the results of spontaneous NB-test (p<0,05).
Fig. 5. Rate of metabolic activity of neutrophils in peripheral blood of cancer patients in
comparison with those of healthy volunteers in spontaneous and induced NB-test (nitrone
blue test) (median, 25%÷75%).
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 167

Peripheral blood NK number enhances at the early stage of sepsis in patients with sepsis
(Giamarellos-Bourboulis E.J. et al., 2006), while in patients with septic shock their relative
number decreases (Holub M. et al., 2000).

5. Apoptosis of the immune cells after trauma

Apoptosis of various immune cells is an important part of immune suppression
development in response to an emergency situation (trauma, burns, infection). Suppression
of active immunity due to the death of monocytes, macrophages and lymphocytes can
enhance risk of opportunistic infections. Moreover, a higher rate of apoptosis in lymphoid
tissues and parenchyma organs may lead to disorders in cellular homeostasis and the
following inadequate response of the organism as a whole including development of
MODS.
Clinical and experimental studies of trauma and burns showed that enhanced production of
endogenous mediators of inflammation (heat shock proteins, free oxygen radicals, NO, TNF,
IL-1 and IL-6) could activate signaling pathways of apoptosis in different immune cells.
Increased expression of apoptotic markers on T-cells (Fas и FasL) was observed in patients
who underwent surgery that makes reason for lymphopenia leading to a higher risk of
post-surgical infections. However, some authors reported about decrease of apoptotic
marker on leukocytes in sepsis and SIRS (Härter L. et al., 2003, Sayeed M.M., 2004,
Papathanassoglou E.D.E. et al., 2005, Jimenez M.F., et al. 1997, Lee WL & Downey GP. ,
2001). The expression level of this marker on neutrophils correlates with the severity of the
inflammation (Fialkow L. et al., 2006). Apparently, alterations in apoptosis regulation as the
process responsible for the elimination of fading cells play an essential role in pathogenesis
of sepsis and multi-organ dysfunction syndrome (Pierozan P. et al.,2006, Mahidhara R. et al,
2000).

6. Platelets in sepsis
Platelets may be considered as a linking chain between innate immunity and homeostasis.
Activated platelets can form clusters in blood circulation system that leads to thromboses
and their sequestration in microcirculation often leads to dessiminated inter-vessel blood
coagulation.
Systemic capillary thrombosis in situation of inter-vessel blood coagulation is one of the
reasons for multi-organ dysfunction. Moreover, extended and long-term activation of the
coagulation system results in exhausted factors of coagulation and platelet function, which
causes increased bleeding.

7. Immunoglobulins
Imbalance of humoral immunity that develops in sepsis presents quantitative and
qualitative changes in serum immunoglobulins. A lot of authors report about reduction of
immunoglobulins A, G, М and their subtype levels in SIRS (Kyles B.D.M.& Baltimore J.,
2005, Tabata N. et al., 1995). The results of a prospective study (Dietz S. et al., 2010) of 543
patients with sepsis demonstrated that half of them had physiological normal IgG level in
peripheral blood (6,1-11,9 g/dL). However intra-venous infusion of immunoglobulins in
168 Insight and Control of Infectious Disease in Global Scenario

patients with systemic inflammatory processes is widely used (Berlot G. et al, 2007, Jenson
H.B., 1998, Pildal J.& Gotzsche P.C., 2008). On the other hand, some authors state that there
was no reliable increase of survival in patients with sepsis after treatment with exogenous
immunoglobulins (Alejandria M.M. et al., 2002, Werdan K., 1999).

8. Immunological imbalance in patients with sepsis

At present there is a standpoint of the massive inflammatory reaction as a result of systemic
release of cytokines that is the basic cause for MODS (Goris J.A. et al., 1985). A MODS is the
result of endothelial cell damage, impairment of vessel penetrative capacity, micro circular
disorders with developing cellular hypoxia and finally, cell apoptosis with the release of
immune or necrotic proteins. Kidneys and gastro-intestinal tract are highly sensitive to
micro-circular disorders, which lead to necrosis of renal tubules that enhances
concentration of serum creatinine, develops oliguria or anuria and necrosis of intestine
fringes. Excessive inflammatory reaction may change to areactivity that leads to immune
suppression (and even to immunological paralysis) and joining secondary infection.
Pathological morphological analysis often cannot detect correspondence between
histological results and the grade of organ dysfunction registered in patients who died from
sepsis. The number of dead tissue cells of heart, kidneys, liver and lungs can be insignificant
to reflect the marked organ dysfunctions. Apparently, most symptoms of organ
dysfunctions in patients with sepsis can be due to "cell hibernation" or "cell stunning” in the
way it happens in myocardial ischemia (Sawyer DB & Loscalzo J., 1985). Reactions that are
observed in septic conditions can be also seen in other pathological processes that are not
directly linked to effects of microbes or their products, such as trauma, shock, advanced
surgical interventions. Therefore the correct definition of sepsis is crucial because different
approach to understanding sepsis leads to different treatment strategy (primarily, anti-
bacterial) and directly effects the outcome. Biological response to microbial components at
the beginning of SIRS and sepsis is considered to be immunological reaction of the body in
order to reduce the number of pathogens. However unrestricted and excessive production
of pro- and anti-inflammatory mediators plays the major role in pathogenesis of sepsis and
MODS. Therefore treatment of sepsis should involve control of mediators of inflammatory
cascade. Microbial components (such as endotoxin, etc.) and other mediators of
inflammation (cytokines, chemokines, leukotriens, thromboxanes, platelet activating factor)
that induce systemic inflammatory syndrome should be eliminated at the early stage of
sepsis. Some authors proposed restriction of excessive activation of immune system of
patients with sepsis by inhibiting various elements of inflammatory cascade. Monoclonal
antibodies against LPS and TNF and other biological regulatory factors were offered to
achieve the desired effect. However randomized clinical studies did not show clinical
effectiveness of such agents (Vincent J.-L.&Abraham E., 2006). Another promising
approach is the use of selective haemosorption with LPS-absorbers that allow elimination of
a large part of bacterial toxins and inflammatory mediators from patient’s peripheral blood.

9. Haemosorption with LPS-adsorber for elimination of triggers and

mediators of inflammation in patients with sepsis and SIRS
Endotoxin (lipopolysaccharide, LPS) is well known as the main biological substance causing
Gram-negative septic shock. The lack of clinical success in anti-endotoxin therapies with
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 169

antibodies determined the development of extracorporeal methods aimed at reducing the

circulating endotoxin level by adsorption. Theoretically such procedures could prevent
progression of the systemic inflammatory reaction due to the elimination of inflammation
trigger factors and mediators (cytokines, bacterial exo- and endotoxins) from the patient’s
body. The necessity of eliminating a wide spectrum of substances characterized by different
physical and chemical features from blood stipulates the application of non-selective and
non-specific methods such as haemosorption. In current clinical practice some devices for
haemosorption are used as specific (LPS) adsorbers. Launched in 2006 the Alteco® LPS
Adsorber (Alteco Medical AB, Sweden; class IIa medical device) is based on a tailor-made
synthetic peptide which is non-toxic and adsorbs endotoxin selectively in a recommended
single 2-h treatment with a blood flow of 100–200 ml/min and activated clotting time of
≥180 s (information provided by the manufacturer).
Data available confirmed an effective reduction in the LPS level in the patients’ blood after
this procedure (Yaroustovsky M, 2009, Andersen T.H., 2009). In particular, Kulabukhov VV
et al. demonstrated almost total elimination of LPS from the patient’s blood (from 1.44
EU/ml before treatment to 0.03 EU/ml post treatment) (Kulabukhov VV., 2008). This effect
was accompanied by a reduction in procalcitonin and inflammatory cytokines levels. Also,
an obvious improvement was observed in the patient’s haemodynamics.
The same results were shown in the work of T. Ala-Kokko et al.( T. Ala-Kokko, 2009). The
mean total duration of vasopressor infusion was 46 h shorter in the treatment group
compared with the control group (95% CI, 104–12 h, p = 0.165), with an average vasopressor
requirement period of 17.4 ± 6.8 h (95% CI, 5.8–23.8 h) following the start of adsorption
treatment. The level of LPS decreased in all cases except in one study patient and all were
without vasopressors at 24 h. The decrease in the Sequential Organ Failure Assessment
(SOFA) score was 3.4 ± 1.7 from baseline to 24 h after the treatment. The average period of
hospital stay was 3.4 days shorter in the treatment group (95% CI, 21.7–14.8 days, p = 0.881).

Fig. 6. Inverse correlation of MAP dynamics and vasopressor requirement before and after
haemosorption by Alteco.

We studied LPS adsorbers for treating 7 patients with sepsis or septic shock. During the
course of extracorporeal detoxification a number of clinical parameters were estimated.
170 Insight and Control of Infectious Disease in Global Scenario

These were temperature, mean arterial pressure (MAP), central venous pressure (CVP), the
percentage of available haemoglobin saturated with oxygen (SaO2), the fraction of inspired
oxygen (FiO2), the partial pressure of oxygen in arterial blood (PaO2), PaO2/FIO2 ratio (an
index to characterize the acute respiratory distress syndrome), severe hypoxaemia
(insufficient oxygen content in blood), the biochemical parameters of blood (lactate,
procalcitonin (PCT)), and concentrations of LPS and cytokines in blood. The requirement for
vasopressors (Dopamine, Norepinephrine) was also evaluated.
Data shown in Table 2 and Figure 6 unambiguously demonstrated a pronounced tendency
towards the oxygen saturation of haemoglobin (SaO2) and normalization of the oxygen
index (decreasing FiO2 on 22%). This was associated with a rise in MAP and a decrease in
CVP. Normalization of cardio-vascular system function led to a reduction in the
requirement for vasopressors.

Parameters Before hemosorption After hemosorption p

CVP, mm Hg 16±5.0 12±4.1 >0.05
SaO2 ,% 87±6.1 94±5.9 >0.05
FiO2 ,% 77±32.3 55±15.4 <0.05*
PaO2/FiO2 160±70.9 200±54.1 <0.05*
PCT ng/ml 22±14.3 12±6.0 >0.05
Lactate, mmol/l 4.3±1.3 4.5±3.2 >0.05
* Significant difference
Table 2. Clinical parameters before/after haemosorption by Alteco.

Fig. 7. The body temperature values for patients before and after haemosorption by
Alteco.

The significant increase in the respiratory index (РaO2/FiO2) after haemosorption

evidenced the improvement of oxygen diffusion through the alveoli-capillary membrane.
As a result, normalization of integral indices, such as body temperature and blood PCT
level, was observed (Fig.7).
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 171

The level of LPS, the key trigger signal for system inflammatory reaction, decreased by a
factor of 2 to 3 versus control after haemosorption (Fig.8).

1.5
EU/ml

0.5

0
before HS after HS Washout

Fig. 8. LPS level in the blood of patients with sepsis before and after haemosorption by
Alteco.

As hypercytokinaemia determines the development of SIRS, it seems to be possible that

reducing cytokine levels (IL-8, IL-1β, IL-6, IL-10 etc) in blood may block the generalization
of this pathological process or interrupt the cascade of cytokine storm. We studied the
influence of haemosorption on the cytokine content in blood (Fig. 9).
Equal portions of sorbent were suspended in equal volumes of physiological solution (0.9%
NaCl) and put onto the shaker during temperature control. High levels of some cytokines
(IL-6, IL-8, IL-12, INFγ and TNF) were indicated in the supernatant (Fig.9).
We also investigated washouts from a sorbent after the termination of the haemosorption
procedure. There were no well-developed specific conditions for the extraction and
quantitative estimation of the characteristics of the sorbent.
This approach was especially informative in cases in which the level of analyte was higher
in the blood after haemosorption than before the treatment (see examples in Fig. 9).
Moreover, an increase in the concentration of some soluble cytokine receptors (sIL-1 II R,
sIL-6 R) was observed in patient blood after haemosorption (Fig. 10).
We assumed that this phenomenon was determined by the release of cytokines from their
complexes with receptors or proteins during the course of haemosorption.
172 Insight and Control of Infectious Disease in Global Scenario

IL-10 IL-8

IL-1β IL-6
Fig. 9. The levels of cytokines in the blood of patients with sepsis before and after
haemosorption by Alteco.

sIL-1 II R sIL-6 R
Fig. 10. Serum levels of soluble receptors in the blood of patients with sepsis before and after
haemosorption by Alteco.
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 173

Our results indicated that low levels of serum cytokines revealed by ELISA did not reflect
the real content of these mediators of inflammation in the blood of patients with septic
complications. Perhaps a high secretion of cytokines was accompanied by an increase in the
expression of congruent receptors, which bound a significant quantity of free cytokines in
ligand-receptor complexes capable of dissociation. We showed that extracorporeal
detoxification using the Alteco device allowed the elimination not only of free cytokines, but
also the majority of bound endogenous bioregulators from cytokine/receptor complexes.
Removal of the trigger factor (LPS) along with a wide range of pro- and anti-inflammatory
cytokines, and possibly with other inflammation mediators (leukotrienes, thromboxanes, C-
reactive protein) led to the interruption of the systemic inflammatory reaction, which was
regarded as positive clinical effect of haemosorption for extracorporeal detoxification.
Correlation analysis demonstrated a close connection between the concentrations in blood of
LPS and TNFα (p= 0.050), LPS and IL-8 (p= 0.050). During the study, a 28-day survival of 9
critical patients was 96%, only 1 patient died after the procedure.
Taking into account a high correlation of normalized clinical parameters and the dynamics
of LPS level and the serum profile of cytokines, the testing parameters (serum levels of IL-
6,TNFα, IL-8) could be considered additional indicators of patient’s status during the course
of treatment, including methods of extracorporeal detoxification.
We assumed that changes in serum concentrations of cytokines after haemosorption might
influence the functional activity of immune cells. Neutrophils and natural killers (NK) play
a crucial role in pathogenesis of organ and multi-organ failures in case of sepsis. Our results
demonstrated a pronounced tendency towards normalization of the functional activity of
these innate immunity effectors after haemosorption by Alteco. Thus, phagocytic number
(PN) and phagocytic index (PI) decreased after haemosorption in 1.3 – 2.1 times and 2.1 – 2.6
times, respectively. A reduction in spontaneous neutrophil activity was also observed. This
parameter indicates the intensity of oxygen-dependent phagocytosis associated with the
release of free radicals destroying the adjacent cells including endothelium. Moreover, the
decrease was observed in the super-aggressive non-specific reaction of NK: index of
cytotoxic activity (ICA) reduced after haemosorption from 75-90% to 54-58% (normal for
healthy volunteers). This effect of normalizing functional activity of neutrophils and NK is
likely connected with the elimination of LPS molecules and cytokines from peripheral
blood.
Stimulation of immune cells for a long period could lead to exhaustion of their killing
activity, resulting in the circulation of leukocytes that are unable to provide defence
functions, such as termination of phagocytosis and killing transformed cells. These “ballast”
cells do not express apoptosis receptor CD95 on their surface membrane, and consequently
they cannot be eliminated from system circulation.
It was shown previously that prolongation of life of leukocytes could produce tissue and
organ damage in case of SIRS and sepsis. A change in apoptosis regulation may influence
pathogenesis of sepsis and multi-organ failure. We demonstrated the increase in
СD45+CD95+ cell number (from 21-24% to 38-40%) after haemosorption. After the
treatment, the number of CD45+CD66b+CD95+ neutrophils was higher by 32-42%, which
correlated with an increase in the number of phagocytes able to terminate oxygen-
dependent phagocytosis. Correlation analysis revealed a strong connection between these
parameters (р=0.0086).
174 Insight and Control of Infectious Disease in Global Scenario

Therefore, reduction of the functional activity of leukocytes (PN, PI, ICA) to the level of that
of healthy individuals and simultaneous increase in CD95+ leukocyte level could be
considered a favourable prognostic factor.
The obtained results demonstrated that the LPS adsorber could effectively eliminate a wide
range of the factors from peripheral blood (such as LPS, cytokines, etc.), which mediate all
the stages of systemic inflammatory reaction in the body. Significant improvement of the
performance status of patients with sepsis was observed after extracorporeal detoxification
with LPS adsorber. This was the normalization of cardio-respiratory functions and
reduction in hyperthermia and vasopressor requirement, normalization of MAP and
concentration of gases in peripheral blood.

10. Conclusion
The discussed data and information show that cancer patients with sepsis have an enhanced
serum level of LPS as compared to healthy volunteers. There is a close link between a
decreased serum level of LPB along with the 10-fold reduction of LPB/LPS ratio and poor
prognosis in cancer patients with sepsis. A characteristic cytokine profile of septic condition
demonstrated that IL-6, IL-18 and soluble receptor sTNF RI concentrations significantly
exceeded those of healthy volunteers and therefore high serum concentrations of IL-6, IL-8,
IL-10, sTNF RI, sIL-1 RII, and sIL-6 R could be suggested as markers of sepsis for cancer
patients.
In conclusion, triggers and mediators of inflammation secreted by immune cells play a
crucial role in pathogenesis of SIRS and sepsis. Management of the inflammatory cascade
should be considered an essential part of the complex approach to the treatment of systemic
suppurative septic complications.

11. References
Alejandria M.M., Lansang M.A., Dans L.F., Mantaring J.B.V. Intravenous immunoglobulin
for treating sepsis and septic shock. Cochrane Database Syst Rev. 2002;CD001090.
Alves-Filho J.C., Spiller F., Cunha F.Q. Neutrophil paralysis in sepsis. Shock. 2010;34 (Suppl
1):15-21.
Andersen T.H., Jensen T.H., Andersen L.W. Adjunctive therapy of severe sepsis and septic
shock in adults Current Anaesthesia & Critical Care Volume 20, Issues 5-6, 2009, P.
254-258
Anderson R., Schmidt R. Clinical biomarkers in sepsis. Front Biosci (Elite Ed). 2010 1;2:504-
520.
Anderson R., Schmidt R. Clinical biomarkers in sepsis. Front Biosci (Elite Ed). 2010 1;2:504-
20.
Angus D.C., Linde-Zwirble W.T., Lidicker J., Clermont G., Carcillo J., Pinsky M.R.
Epidemiology of severe sepsis in the United States: analysis of incidence, outcome,
and associated costs of care. Crit Care Med. 2001; 29: 1303–1310.
Annane D, Bellissant E, Cavaillon J-M. Septic shock. Lancet. 2005; 365: 63-78.
Balzan S., Quadros C. D. A., Cleva R.D., Zilberstein B., Cecconello I. Bacterial translocation:
Overview of mechanisms and clinical impact Issue J Gastroenterol Hepatol. 2007;
22(4): 464–471.
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 175

Barber M.D., Fearon K.C., Ross J.A. Relationship of serum levels of interleukin-6, soluble
interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase
protein response in advanced pancreatic cancer. Clin Sci (Lond). 1999 ;96(1):83-87.
Barber M.D., Fearon K.C., Ross J.A. Relationship of serum levels of interleukin-6, soluble
interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase
protein response in advanced pancreatic cancer. Clin Sci (Lond). 1999 ;96(1):83-87.
Berlot G., Bacer B., Piva M., Lucangelo U., Viviani M. Immunoglobulins in sepsis Adv In
Sepsis. 2007; 6 (2): 41-46.
Calandra T., Baumgartner J.D., Grau G.E., Wu M.M., Lambert P.H., Schellekens J., Verhoef
J., Glauser M.P. Prognostic values of tumor necrosis factor/cachectin, interleukin-1,
interferon-alpha, and interferon-gamma in the serum of patients with septic shock.
J Infect Dis. 1990;161(5):982-987.
Deitch EA, Bridges RM. Effect of stress and trauma on bacterial translocation from the gut. J
Surg Res 1987; 42 (5): 536–42
Dietz S., Lautenschlaeger C., Mueller-Werdan U., Werdan K. Low levels of immunoglobulin
G in patients with sepsis or septic shock: a signum mali ominis? Crit Care. 2010;
14(Suppl 1): P26.
Emoto M., Miyamoto M., Yoshizawa I., Emoto Y., Schaibe U.E., Kita E., Kaufmann S.H.E.
Critical role of NK cells rather than Vα14+NKT cells in lipopolysaccharide-induces
lethal shock in mice. J Immunol. 2002; 169:1426-1432.
Fialkow L., Filho L.F., Bozzetti M.C., Milani A.R., Filho E.M.R., Ladniuk R.M., Pierozan P.,
de Moura R.M.,Prolla J.C., Vachon E., Downey G.P. Neutrophil apoptosis: a
marker of disease severity in sepsis and sepsis-induced acute respiratory distress
syndrome Crit Care. 2006; 10(6): R155.
Frieling J.T.M., Van Deuren M., Wijdenes J. Circulating interleukin-6 receptor in patients
with sepsis syndrome. J Infect Dis 1995; 171:469-472.
Frieling J.T.M., Van Deuren M., Wijdenes J. Circulating interleukin-6 receptor in patients
with sepsis syndrome. J Infect Dis 1995; 171:469-472.
Gaïni S., Koldkjaer O.G., Pedersen C., Pedersen S.S. Procalcitonin, lipopolysaccharide-
binding protein, interleukin-6 and C-reactive protein in community-acquired
infections and sepsis: a prospective study. Crit Care. 2006;10(2):R53.
Giamarellos-Bourboulis E.J. What is the pathophysiology of the septic host upon admission?
Int J Antimicrob. Agents. 2010;36 (2):S2-54.
Giamarellos-Bourboulis E.J., Tsaganos T., Spyridaki E., Mouktaroudi M., Plachouras D.,
Vaki I., Karagianni V., Antonopoulou A., Veloni V., Giamarellou H. Early
changes of CD4-positive lymphocytes and NK cells in patients with severe Gram-
negative sepsis. Crit Care. 2006; 10: R166.
Giamarellos-Bourboulis EJ What is the pathophysiology of the septic host upon admission?
Int J Antimicrob Agents. 2010 Dec;36 Suppl 2:S2-54;
Goris J.A., te Boekhorst T.P.A., Nuytinck J.K.S. Multiple organ failure: generalized
autodestructive inflammation? Arch. Surg. 1985; 120:1109-1115.
Hammond M.E., Lapointe G.R., Feucht P.H., Hilt S., Gallegos C.A., Gordon C.A., Giedlin
M.A., Mullenbach G., Tekamp-Olson P. IL-8 induces neutrophil chemotaxis
predominantly via type I IL-8 receptors. J Immunol. 1995;155(3):1428-1433.
Härter L., Mica L., Stocker R., Trentz O., Keel M. Mcl-1 correlates with reduced apoptosis in
neutrophils from patients with sepsis. J Am Coll Surg. 2003;197:964–973.
176 Insight and Control of Infectious Disease in Global Scenario

Hildebrand F., Pape H.C., Krettek C. The importance of cytokines in the posttraumatic
inflammatory reaction Unfallchirurg. 2005;108(10):793-794, 796-803.
Holub M., Kluèkova Z., Beneda B., Hobstová J., Hužička I., Pražák J., Lobovská A. Changes
in lymphocyte subpopulations and CD3+/DR+ expression in sepsis. Clin Microbiol
Infect. 2000; 6: 657-660.
Jenson H.B., Pollock B.H. The role of intravenous immunoglobulin for the prevention and
treatment of neonatal sepsis. Semin Perinatol. 1998;22:50-63.
Jimenez M.F., Watson W.G., Parodo J., Evans D., Foster D., Steinberg M., Rotstein O.D.,
Marshall J.C. Dysregulated expression of neutrophil apoptosis in the systemic
inflammatory response syndrome. Arch Surg. 1997;132:1263–1270.
Keel M., Trentz O. Pathophysiology of polytrauma, Injury. 2005;36: 691–709.
Kerr A.R., Kirkham L.A.S., Kadioglu A., Andrew P.W., Garside P., Thompson H., Mitchell
T.J. Identification of a detrimental role for NK cells in pneumococcal pneumonia
and sepsis in immunocompromised hosts. Microbes Infect. 2005; 7:845-852.
Kulabukhov VV. Use of an endotoxin adsorber in the treatment of severe abdominal sepsis.
Acta Anaesthesiol Scand. 2008 Aug;52(7):1024-5.
Kumar A.T., Sudhir U., Punith K., Kumar R., Ravi Kumar V.N., Rao M.Y. Cytokine profile in
elderly patients with sepsis. Indian J Crit Care Med 2009;13:74-78.
Kumar V., Sharma A. Neutrophils: Cinderella of innate immune system. Int
Immunopharmacol. 2010; 10: 1325-1334.
Kyles B.D.M., Baltimore J. Adjunctive use of plasmapheresis and intravenous
immunoglobulin therapy in sepsis: a case report american journal of critical care.
2005; 14 (2): 109-112.
Laurenzi L., Natoli S., Di Filippo F., Calamaro A. Systemic and haemodynamic toxicity after
isolated limb perfusion (ILP) with TNF-alpha. J Exp Clin Cancer Res. 2004;23(2):
225-231.
Lee WL, Downey GP. Neutrophil activation and acute lung injury. Curr Opin Crit Care.
2001;7:1–7
Lenz A., Franklin G.A., Cheadle W.G. Systemic inflammation after trauma Injury. 2007
Dec;38(12): 1336-1345.
Mahidhara R., Billiar T.R. Apoptosis in sepsis. Crit Care Med. 2000;28:N105–N113.
Martin C., Saux P., Mege J.L., Perrin G., Papazian L., Gouin F. Prognostic values of serum
cytokines in septic shock. Intensive Care Med. 1994;20(4):272-977.
Martin C., Saux P., Mege J.L., Perrin G., Papazian L., Gouin F. Prognostic values of serum
cytokines in septic shock. Intensive Care Med. 1994;20(4):272-977.
Moore F.A. The role of the gastrointestinal tract in postinjury multiple organ failure// Am.
J. Surg. 1999; 178: 449–453.
Müller B., Peri G., Doni A., Perruchoud A.P., Landmann R., Pasqualini F., Mantovan A.
High circulating levels of the IL-1 type II decoy receptor in critically ill patients
with sepsis: association of high decoy receptor levels with glucocorticoid
administration. J Leukocyte Biol. 2002;72:643-649
Murphy R., DeCoursey T. E. Charge compensation during the phagocyte respiratory burst.
Bioenergetics. 2006; 1757( 8): 996-1011.
Myc A., Buck J., Gonin J., Reynolds B., Hammerling U., Emanuel. The level of
lipopolysaccharide-binding protein is significantly increased in plasma in patients
Immunological Pathogenesis of Septic Reactions
and Elimination of Triggers and Mediators of Inflammation 177

with the systemic inflammatory response syndrome. Clin Diagn Lab Immunol.
1997; 4:113–116.
Nijhuis C. S., Vellenga E., Daenen S.J., Graaf W.T., Gietema J.A., Groen H. J., Kamps W.A.,
Bont E. Lipopolysaccharide-binding protein: a possible diagnostic marker for
Gram-negative bacteremia in neutropenic cancer patients Intensive Care Medicine
2003; 29, 12: 2157-2161.
Oppenheim J.J., Yang D. Alarmins: chemotactic activators of immune responses. Curr Opin
Immunol. 2005; 17: 359-365.
Papathanassoglou E.D.E., Moynihan J.A., McDermott M.P., Ackerman M.H. Expression of
Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness
and association with multiorgan dysfunction severity and survival. Crit Care Med.
2001;29:709–718.
Pildal J., Gotzsche P.C. Polyclonal immunoglobulin for treatment of bacterial sepsis: a
systematic review. Clin Infect Dis. 2004;39:38-46.
Pinsky M.R. Pathophysiology of sepsis and multiple organ failure:pro- versus anti-
inflammatory aspects. Contrib. Nephrol. 2004; 144: 31-43.
Quinn J.V., Slotman G.J. Platelet-activating factor and arachidonic acid metabolites mediate
tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction
during bacteremic shock. Crit Care Med. 1999;27(11):2485-2494.
Rigato O., Ujvari S., Castelo A., Salomão R. Tumor necrosis factor alpha (TNF-α) and sepsis:
Evidence for a role in host defense. Infection. 1996; 24: 314–318.
Rigato O., Ujvari S., Castelo A., Salomão R. Tumor necrosis factor alpha (TNF-α) and sepsis:
Evidence for a role in host defense. Infection. 1996; 24: 314–318.
Sawyer DB, Loscalzo J. Myocardial hibernation: restorative or preterminal sleep?
Circulation. 2002; 105(13): 1517-1519.
Sayeed M.M. Delay of neutrophil apoptosis can exacerbate inflammation in sepsis patients:
cellular mechanisms. Crit Care Med. 2004;32:1604–1606.
Segal A.W. How neutrophils kill microbe. Ann Rev Immunol 2005;23:197–223.
Segal A.W. How neutrophils kill microbe. Ann Rev Immunol 2005;23:197–223.
T. Ala-Kokko, J. Koskenkari and J. Laurila, Lipopolysaccharide adsorber in abdominal septic
shock, Crit Care 13 (Suppl. 1) (2009), p. 280.
Tabata N., Azuma E., Masuda S.-I., Ido M., Sakurai M. Transient low level of IgG3 induced
by sepsis Pediatrics International. 1995; 37(2): 201–202.
Takeshita S., Tsujimoto H., Kawase H., Kawamura Y., Sekine I. Increased Levels of
lipopolysaccharide binding protein in plasma in children with kawasaki disease
Clin Diagn Lab Immunol. 2002; 9(1): 205–206.
Thomas S., Balasubramanian K. A. Role of intestine in postsurgical complications:
involvement of free radicals. Free Rad Biol Med. 2004; 36 (6): 745-756.
Vincent J.-L., Abraham E. The last 100 years of sepsis Am J Resp Crit Care Med. 2006; 173:
256-263.
Volk H.D., Reinke P., Döcke W.D. Immunological monitoring of the inflammatory process:
Which variables? When to assess. Eur J Surg Suppl. 1999; 584:70-72.
Werdan K. Immunoglobulins in Sepsis: Therapeutic Use of Immunoglobulins. Sepsis. 1999;
3, 3:239-245.
Yaroustovsky M, Abramyan M, Popok Z, Nazarova E, Stupchenko O, Popov D, Plushch M,
Samsonova N. Preliminary report regarding the use of selective in complex cardiac
178 Insight and Control of Infectious Disease in Global Scenario

surgery patients with extensive sepsis and prolonged intensive care stay. Blood
Purif. 2009;28(3):227-33.
Yegenaga I., Hoste E., Van Biesen W., Vanholder R., Benoit D., Kantarci G., Dhondt A.,
Colardyn F., Lameire N.: Clinical characteristics of patients developing ARF due to
sepsis/systemic inflammatory response syndrome: Results of a prospective study.
Am J Kidney Dis. 2004; 43 :817 –824.
Yoneda O., Imai T., Goda S., Inoue H., Yamauchi A., Okazaki T., Imai H., Yoshie O., Bloom
E.T., Domae N., Umehara H. Fractalkine-mediated endothelial cell injury by NK
Cells. J Immunol. 2000; 164: 4055-4062.
Zeerleder S., Hack C.E., Caliezi C., van Mierlo G., Eerenberg-Belmer A., Wolbink A.,
Wuillenmin W.A. Activated cytotoxic T cells and NK cells in severe sepsis and
septic shock and their role in multiple organ dysfunctio. Clin Immunol. 2005;116(
2): 158-165.
Zeni F., Tardy B., Vindimian M., Pain P., Gery P., Bertrand J.C. Soluble interleukin-6
receptor in patients with severe sepsis. J Infect Dis. 1995;172(2):607–608.
Zhang B., Huang Y.H., Chen Y., Yang Y., Hao Z.L., Xie S.L. Plasma tumor necrosis factor-α,
its soluble receptors and interleukin-1β levels in critically burned patients. Burns.
1998;24(7):599-603.
Zhang B., Huang Y.H., Chen Y., Yang Y., Hao Z.L., Xie S.L. Plasma tumor necrosis factor-α,
its soluble receptors and interleukin-1β levels in critically burned patients. Burns.
1998;24(7):599-603.
Zucker T., Kriger G. Sepsis-like syndrome caused by the Russian medication pyrogenal
(Salmonella typhi endotoxin). J Exp Clin Cancer Res. 2004; Isr Med Assoc J. 2003;
5(10):750-751.
Zychlinsky A., Weinrauch Y., Weiss J. Introduction: Forum in immunology on neutrophils.
Microbes and Infection. 2003; 5( 14): 1289-1291.