the glycocalyx affects vascular permeability.
In an experimental study, an increase in urinary
albumin and ultrastructural changes of the
glomerular filtration barrier was observed with
a decreased expression of syndecan-1, hyaluronic
acid and sialic acid, all glomerular glycolic
components. 60 Clinical studies reveal a strong
relationship between deterioration of the
endothelial glycocalyx and severity of sepsis. It
has been related to the activity of TNFα. 61 Renal
cells are especially sensitive; deterioration has
also been described in the lung and hepatic
sinusoidal endothelium. 53
• The intestine: the intestine can house around
500 species of bacteria. 62 The passage of viable
and non-viable micro-organisms, and their
products, such as endotoxins, through the
anatomically intact intestinal barrier is termed
bacterial translocation. It can be a physiological
mechanism of stimulation of the immune system
that under certain conditions can be overcome
and initiate systemic inflammatory processes. 63,64
The intestne comprises 25% lymphoid tissue
and 70–80% of the immunoglobulin-secreting
cells are found in the intestine. For many years,
the intestine was thought to be the ‘motor of
sepsis’. 65 Alteration of intestinal epithelial
integrity, the increase in permeability and
alteration of the gut microbiome are also
documented in sepsis. 66
The response
to infection is
dependent on
the causative
organism(s), the
host’s response
and other
environmental
and therapeutic
factors
Factors affecting response to infection
The response to infection is dependent on factors
associated with the causative organism(s), the
ability of the host to respond and other
environmental and therapeutic factors. 67
Micro-organism
Bacterial products, fundamentally components
of the cell wall, activate the immune system
by manufacturing and releasing inflammatory
mediators responsible for the systemic response.
Endotoxin, or, more precisely, bacterial
lipopolysaccharide (LPS), is recognised as the most
potent microbial mediator involved in the
pathogenesis of sepsis and septic shock. LPS is
a highly antigenic molecule part of the cell wall
of gram-negative bacteria that binds in body
fluids to the soluble binding protein (LBP) that
serves to facilitate its binding to the CD14
monocyte membrane receptor. LBP is dissociated
and the resulting complex makes contact with
the TLR4. Other components of the bacterial
wall are: peptidoglycan, muramyl dipeptide,
and lipoteichoic acid. Other bacterial products
produce a systemic response: Staphylococcal
enterotoxin B, toxic shock syndrome toxin-1,
Pseudomonas exotoxin A, and M protein of
haemolytic group A streptococci. 68
Influenza A virus infection will induce
a pro-inflammatory innate immune response
through the recognition of viral RNA by TLR7 and
retinoic acid-inducible gene 1 (RIG-I) molecules,
that induce the production of the pro-
inflammatory cytokine-mediated NF-κB route and
activate the antiviral response. 52
Host
Immunosuppression is accompanied by an
increased incidence of sepsis and worse
prognosis. 69
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Genetics
Parental death through infection before the age
of 50 years, presents an increased risk of dying
of infection (5.8-times) for an individual. This
observation was made after studying the causes of
premature deaths in 1000 families with adopted
children, verifying the relationship with the
death of the biological parents with that of the
adopted parents. This relative risk is higher than
death due to cancer or cardiovascular diseases,
and suggests a significant genetic susceptibility to
death by infection and, by extension, to sepsis. 70
Other articles extend the studies on gene
polymorphisms of other responsible molecules in
the cell signalling mechanism during the immune
response in the process of systemic inflammatory
response. Polymorphisms in TLR4 and CD14
have been associated with survival and the
development of septic shock. These
polymorphisms would code for proteins with
less responsiveness to lipopolysaccharide. These
patients would present an inadequate early
expression of pro-inflammatory proteins in
response to endotoxin (tolerance to
endotoxin). 71–74
A number of different proteins are involved
in iron metabolism. The delicate connection
between innate immunity and iron homeostasis
might seem obvious, but it is difficult to prove.
It seems certain that a balance between both
systems is fundamental in the defence against
micro-organisms, because poor management of
iron reserves in any cell compartment would be
harmful to the host and beneficial to the invading
pathogen. 75
Modifiable factors
Adipose tissue has a role in immune regulation. 76
It has been observed that adipocytes and some
cells of the immune system, such as T
lymphocytes and macrophages, have similar
characteristics in terms of the production of
pro-inflammatory cytokines. Adipose tissue
secretes biologically active molecules
(adipokines), among which are TNFα, IL-6, leptin
and adiponectin. These molecules participate in
physiological processes including regulation of
energy balance, glucose metabolism and vascular
remodelling, and seem to be involved in a
protective effect observed in obese patients. 77
Leptin, for example, acts directly on macrophages
increasing its phagocytic activity and the
production of pro-inflammatory cytokines.
Adiponectin reduces the activity of macrophages
and occurs in smaller amounts in obese
individuals. 78,79 Pregnant women also have low
levels of adiponectin. This immune alteration is
especially important in influenza A infection. 80
This increased severity of influenza in
pregnant women could explain the increased
susceptibility to infection of this condition.
Indeed, the foetus behaves as a semi-allograft
(expressed as both maternal and paternal
antigens). To avoid rejection, during pregnancy,
there are changes in both innate and adaptive
immunity (immune tolerance and active
suppression of the immune response). 81 They
occur both locally at the maternal–foetal
interface, and systemically. In addition to the
foetus being physically protected by trophoblasts,
local adaptations occur to prevent maternal