figure 2
Immune dysregulation in sepsis
Early multi-organ dysfunction
+
Excessive inflammation
Exaggerated innate immunity
Recuitment of neutrophils
Cytokine production
Ferritin
Innate immunity dysregulation
Persistent inflammation
Decreased cytokine production
Myeloid cell immaturity
Reduced phagocytosis
Moderate inflammation
–
Vulnerability to infection
and death
Moderate immunosuppression
Immunoparalysis
Decreased expression of HLA-DR on monocytes
Cytokine release
Metabolic dysfunction
Adaptive immune suppression
T cell anergy
Lymphocyte apoptosis
Reduced T cell proliferation
Increased Treg
T cell Th1/Th2 polarisation
Late multi-organ dysfunction
immune cells and antibody-mediated cell
destruction: alteration in expression of HLA,
increased expression of soluble
immunomodulators with anti-inflammatory
properties (progesterone, PGE2, and anti-
inflammatory cytokines). Likewise, a change
occurs in lymphocyte populations at the uterine
and systemic levels. 82 Among other mechanisms,
changes in the endocrine status have been
suggested to be an important part of the
machinery responsible for the induction of
immune tolerance during pregnancy. Indeed,
pregnancy-associated hormones, especially
progesterone, are known to confer immune
suppressive capacity to innate as well as adaptive
immune cells. 83 As an example, protease
inhibitors used in HIV-pregnant women interact
with the metabolism of progesterone, decreasing
its production and increasing the risk of maternal
and foetal poor outcomes. 84
Alcohol intake
Chronic alcohol intake increases the incidence
of sepsis and poor prognosis. Alcohol alters
immunological defence mechanisms in the
respiratory tract, causing deregulation of alveolar
macrophages and alveolar epithelial barrier
dysfunction. 85 In a meta-analysis, a 1.89-fold
increase in the odds of ARDS was found in people
who consumed high levels of alcohol. The
mechanisms by which alcohol consumption could
increase the risk of ARDS, particularly among
patients with sepsis, are not fully understood.
Mechanisms described in the literature include:
alteration of alveolar membrane permeability;
glutathione depletion; positive Toll-like receptor
regulation; expression of TGFb1; and impaired
macrophage function. 86
Tobacco
Smokers have higher incidence of sepsis. 87 In
patients with valvulopathies, pro-inflammatory
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cytokines have been found to be elevated. In
experimental models, the acute administration
of nicotine is detrimental in sepsis (CLP model),
possibly because the suppression of inflammation
leaves the host defenceless against microbial
proliferation. 88,89
Vitamins
A low level of vitamin D is associated with an
increased risk of suffering from sepsis and with
a worse prognosis. 90,91 Vitamin D has broad
biological effects on nuclear transcription, cell
cycle regulation, differentiation and apoptosis. 92
and plays a key role in redox regulation and
immunomodulation. 93
Vitamin C is a potent antioxidant and anti-
inflammatory; 94 it decreases the production of
inflammatory mediators through the inhibition
of NF-κB. It is recognised to have an important
role in the preservation of the capilliary
endothelial integrity. Clinically, an important
advantage has been described in the treatment
of septic patients along with corticosteroids. 95,96
Vaccinations
Vaccination has been shown to reduce the
incidence of sepsis caused by certain pathogens
such as Streptococcus pneumoniae, Haemophilus
influenzae type B and Neisseria meningitidis or
influenza A virus. 97 However, access to vaccines
is still difficult in some countries. 98
Conclusions
The pathophysiology of sepsis is extremely
complex. Previously, it was believed that sepsis
was just an exaggerated, hyper-inflammatory
response with mortality arising from
inflammation-induced organ injury. However,
data suggest that heterogeneity exists in septic
patients’ inflammatory responses
(immunostimulation vs immunosuppression),
alongside cellular alterations.