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REVIEW

CURRENT
OPINION Pathophysiology of sepsis
AQ2 Pietro Arina and Mervyn Singer

Purpose of review
To provide a current overview of sepsis pathophysiology.
Recent findings
The emphasis on sepsis pathophysiology has moved away from the pathogen - the initiating factor - and
instead is focussed upon the abnormal and exaggerated host response. Instead of targeted eradication of
the infection, the host response activates or suppresses multiple downstream pathways, leading to multiple
organ dysfunction.
Summary
Sepsis represents a dysregulated host response to infection leading to organ dysfunction. Here, the
pathogen triggers an initial exaggerated inflammatory-immune response that leads to activation or
suppression of multiple endothelial, hormonal, bioenergetic, metabolic, immune, and other pathways.
These, in turn, produce the circulatory and metabolic perturbations resulting in organ dysfunction. This
review will provide an overview of underlying mechanisms and propose that these processes, whereas
superficially viewed as dysfunctional, may actually be adaptive/protective in the first instance, though
spilling over into maladaptation/harm depending on the magnitude of the host response.
Keywords
adaptation/maladaptation, infection, inflammation, organ dysfunction, sepsis

INTRODUCTION Pathogen-Associated Molecular Patterns. These are

Sepsis is a complex clinical and biochemical syn-
drome defined as life-threatening organ dysfunction
caused by a dysregulated host response to infection
[1]. The underlying pathophysiology remains to be
fully elucidated and the influence of both underlying
comorbidities and iatrogenic factors – both positive
and negative – remain unclear. As a consequence,
there has been a paucity of new interventions that
have been shown to clearly benefit septic patients.
This article will attempt to summarize the current
knowledge base, highlight gaps in understanding,
and suggest that dysfunction may represent in part
an adaptive/protective host response to a severe,
overwhelming insult. Restrictions in word count pre-
vent comprehensive coverage so we have focused
upon what we consider to be the critical systems
involved.
identified as alien by extracellular and intracellular
Pattern Recognition Receptors (PRRs) such as the
Toll-like receptor and nucleotide-binding oligomeri-
zation domain-like receptor systems, triggering a
downstream inflammatory response [2]. In addition,
damaged host cells release their constituents, such as
intracellular proteins, DNA, and mitochondria, into
the interstitial and vascular spaces. These Damage-
Associated Molecular Patterns (DAMPs) are also
recognized as alien by the same PRR systems [3,4].
PRRs on immune and endothelial cells trigger
downstream signal transduction pathways, activat-
ing transcription factors such as NF-kB and AP-1,
which enter the nucleus and increase or suppress
transcription of genes that orchestrate inflamma-
tory responses [5]. One such response is the subse-
quent production and release of multiple cytokines
(such as tumor necrosis factor-alpha, interleukin

INFECTION TRIGGERS A HOST

INFLAMMATORY RESPONSE
Infection initiates a host inflammatory response.
This is commonplace but is usually localized, well-
controlled, and protective. Microorganisms or their
constituents (such as Gram-negative bacterial lipo-
polysaccharide, or fungal beta-D-glucan) represent
Bloomsbury Institute for Intensive Care Medicine, Division of Medicine, AQ3
University College London, London, UK
Correspondence to Mervyn Singer, Bloomsbury Institute for Intensive
Care Medicine, University College London, Cruciform Building, Gower AQ4
St, London WC1E 6BT, UK. E-mail: m.singer@ucl.ac.uk
Curr Opin Anesthesiol 2021, 33:000–000
DOI:10.1097/ACO.0000000000000963

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Intensive care and resuscitation
KEY POINTS
 Sepsis represents a dysregulated host response to
infection leading to life-threatening organ dysfunction.
 In sepsis the pathogen triggers an initial exaggerated
inflammatory-immune response that leads to activation
or suppression of multiple pathways (endothelial,
hormonal, bioenergetic, metabolic, immune) that, in
turn, produce the circulatory and metabolic
perturbations resulting in organ dysfunction.
 Although dysfunction and failure carry negative
connotations, there is increasing evidence that this may
be in part an adaptive/protective strategy in the face of
a severe, prolonged inflammatory insult.
(IL)-1 and interferon-gamma), chemokines, and
other mediators. Under controlled circumstances,
the innate immune response is promptly activated
with circulating immune cells such as macrophages,
monocytes, neutrophils, and natural killer cells
attracted to the site of infection to phagocytose
and remove both microorganisms and damaged
host cells [6]. The complement system is activated
to aid identification of the pathogen and promote
phagocytosis [6,7]. In addition, the adaptive immune
system is triggered by presenting antigen via den-
dritic and other cells to B and T lymphocytes, thereby
stimulating production of targeted antibodies
(immunoglobulins) and providing memory for sub-
sequent infection by the same pathogen [6].
The endothelium aids this process by also becom-
ing activated, with increased expression of molecules
AQ5 such as E-selectin, VCAM-1 and ICAM-1 that enable
adhesion of immune cells to the endothelial surface
[8,9]. The gap junctions between endothelial cells
widen, allowing ingress of leukocytes and plasma
(containing complement, nutrients, and other fac-
tors) through the blood vessel wall and into the tissues
where the infection is located. A further consequence
of endothelial activation is increased release of Von
Willebrand factor, thromboxanes and other pro-coag-
ulant mediators, and altered bioavailability of nitric
oxide. Damage to the endothelium exposes subendo-
thelial tissue factor, which also activates circulating
clotting factors. The net result is platelet aggregation
and adhesion, stimulation of coagulation pathways,
and formation of microvascular thrombi that prevent
systemic spread of the pathogen.
Body systems are mobilized with, for example,
malaise to encourage changes in behavior such as
resting, pyrexia to enhance bacterial killing, and
activation of systemic hormonal and acute stress
responses with generation of acute-phase proteins
by the liver such as C-reactive protein, complement,
2 www.co-anesthesiology.com
ferritin and fibrinogen [10]. These aids the immune
response, helping to destroy or inhibit growth of
pathogens, stimulating chemotaxis, coagulation,
and vascular permeability.
As a consequence of all the above, microorgan-
isms are promptly identified, host immune defenses
are mobilized to eradicate the pathogens, and clotting
activated to keep the infection localized. To provide
appropriate checks and balances the cells also gener-
ate anti-inflammatory cytokines (e.g. IL-10) and other
mediators (e.g. prostaglandins) to appropriately con-
trol the inflammatory response. This entire process is
extremely complex and needs fine regulation. Mac-
rophage phenotype and function are polarized by the
microenvironment at the site of infection [11]. M1
(‘classically activated’) macrophages maintain
active inflammation with release of pro-inflamma-
tory cytokines whereas M2 (‘alternatively activated’)
macrophages mainly release anti-inflammatory cyto-
kines to reduce inflammation. M2 macrophages pre-
dominate in the later phase of inflammation to clean
up the damage, remove debris and neutrophils. There
is also ingress of fibroblasts to produce local healing
and fibrosis.
The type of pathogen will influence local host
responses and tissue damage. For example, the
SARS-Cov-2 virus directly invades lung alveolar type
II cells resulting in apoptotic death with release/
spread of the virus to other type II cells thereby
generating diffuse alveolar damage with fibrin-rich
hyaline membranes and some multinucleated giant
cells [12]. On the other hand, some strains of Staph-
ylococcus aureus can release the Panton–Valentine
leukocidin exotoxin that not only causes local tissue
necrosis but also destroys leukocytes resulting in a
necrotizing pneumonia [13].
The important concepts of host resistance (ability
to limit pathogen burden through the inflammatory
response) and tolerance or resilience (ability to toler-
ate an equivalent pathogen load by limiting the
harmful consequences of inflammation) merit some
mention here [14,15]. A striking example of tolerance
is asymptomatic bacteremia with highly pathogenic
organisms such as meningococci. Resistance and
tolerance are generally inversely correlated to each
other, and a necessary trade-off must exist between
these two opposing strategies.
SEPSIS AND THE DYSREGULATED HOST
RESPONSE
For reasons still unknown, the appropriate inflam-
matory/immune processes that deal with infection
become dysregulated and compromise both the
affected organ as well as distant organs leading
to functional abnormalities and potentially
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AQ1
life-threatening consequences. Genetic and envi-
ronmental factors, age, sex, comorbidities and
frailty, nutritional status, medications (e.g. immu-
nosuppressants), pathogen load and virulence, and
the site of infection all contribute to a marked inter-
individual variation in response.
Overactivation of PRRs in sepsis leads to either
excessive production or suppression of cytokines,
hormones, and other mediators that often have
contrasting effects. For example, these molecules
can either boost or suppress inflammation [6], be
pro- or anticoagulant [9], or cause microvascular
vasodilation or vasoconstriction [16]. There may
be overspill of cytokines and other signaling medi-
ators into the circulation via blood or lymph drain-
ing from the affected locus of infection, and thence
to vascular beds in unaffected organs. The liver,
which is particularly rich in tissue macrophages
(Kupffer cells) and the main site of acute-phase
protein production, is activated by translocation
of microorganisms and lipopolysaccharide arising
from the gut lumen [17], whereas the lung is the first
downstream organ bed to receive blood draining
from both the liver and lymph returning to the
blood [18]. Bacteria and other pathogens (intracel-
lular or free-floating) can also spread around the
body through blood and lymphatic systems [17–
19]. However, it is important to stress that the
number of bacteria circulating during a bacteremia
is scanty and infrequently exceed 100 colony form-
ing units per ml [20,21]. These are far outnumbered
by the millions of leukocytes within each milliliter
of blood. Thus, bacteremia represents an issue with
normal immune surveillance rather than, in most
patients, a concern about hematogenous spread.
Over-production of IL-6 plus other cytokines will
excessively boost production of acute-phase proteins
by the liver [10]. Biomarkers of inflammation also
play an important biological role. For example, C-
reactive protein promotes hypotension and changes
in intracellular calcium signaling, cytokine produc-
tion, phagocytosis, and complement activation
[22,23] whereas procalcitonin induces cytokine pro-
duction and decreases neutrophil migration [24]. An
imbalance between sympathetic and parasympa-
thetic pathways can compromise neural control of
inflammation and immunity [25,26]. Hormonal
changes modify immune, metabolic, cardiovascular,
and behavioral responses. Gene transcription is also
&
affected and this varies markedly by organ [27 ].
Notably, more genes are down-regulated than up-
regulated during sepsis and gene expression fluctu-
ates widely over the course of the septic illness.
Nonsurvivors in general exhibit similar metabolomic
and proteomic patterns to survivors, though the
magnitude of up- or downregulation is greater
0952-7907 Copyright ß 2021 Wolters Kluwer Health, Inc. All rights reserved.
Pathophysiology of sepsis Arina and Singer
&
[28 ]. The net effect of all the above changes is wide-
spread stimulation or suppression of multiple path-
ways (Fig. 1) leading to dysfunction affecting
multiple organs within the body (Fig. 2). Why some
organs are affected more than others in an individual
patient remains unexplained.
CARDIOVASCULAR DYSFUNCTION CAN
LEAD TO ORGAN HYPOPERFUSION AND
TISSUE HYPOXIA
Changes occur at both macro- and microvascular
levels. The heart can be directly affected, resulting in
myocardial depression affecting, to varying degrees,
left and right ventricles and systolic and diastolic
dysfunction [29]. Mechanisms underlying this so-
called ‘septic cardiomyopathy’ include coronary
microvascular changes, adrenergic pathway down-
regulation, oxidative and nitrosative stress, abnor-
malities in calcium handling and myofilament
sensitivity, downregulation of sarcomeric and mito-
chondrial genes, and mitochondrial dysfunction.
Myocardial depression can be severe enough to
compromise blood flow to the body’s organs, result-
ing in organ hypoperfusion. In the early phases of
sepsis, increased vascular permeability can result in
excessive leak of circulating fluid and oncotic pro-
teins into interstitial extravascular spaces, resulting
in tissue edema and often significant hypovolemia.
This can be further compounded by the loss of body
fluids through sweating, vomiting, diarrhea, gut
ileus, and excessive mouth breathing, as well as
decreased intake through the loss of appetite.
Blood flow is also affected by alterations in
vascular tone and responsiveness to catecholamines
(‘vascular hyporeactivity’). Multiple mechanisms
are recognized including excessive production of
nitric oxide through induction of inducible nitric
oxide synthase, opening of potassium channels, and
downregulation of adrenergic receptors [30]. This
loss of vascular tone, over and above co-existing
myocardial depression and hypovolemia, may result
in hypotension and organ hypoperfusion.
There are downstream irregularities in the micro-
vasculature with patchy areas of constriction and
dilatation. Blood flow to different microcirculatory
areas within the same organ bed may be largely
absent, sluggish, or increased [16]. This may result
in increased shunting of oxygenated blood, bypass-
ing the cells and inducing a local tissue hypoxia in
addition to concurrent macrocirculatory deficiencies
that may compromise regional blood flow. Of note,
clotting pathways are activated and are frequently
identified in abnormal laboratory tests [31]. Indeed,
there is a prothrombotic tendency in sepsis with an
increased incidence of thromboembolism, in part
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FIGURE 1. The infectious insult triggers an initial inflammatory/innate immune response that leads to downstream activation
or suppression of multiple pathways resulting in circulatory and metabolic perturbations. Depending on the magnitude of the
host response, these perturbations may be controlled and appropriate, or dysregulated leading to increasing degrees of organ
dysfunction/failure. An increasing view holds that dysfunction – or, more precisely, an organ metabolic shutdown that
prevents normal cellular activity - may represent in part an adaptive response that protects the organ from permanent,
irreversible damage and permits the opportunity of recovery.

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FIGURE 2. Sepsis can affect functioning of multiple organs within the body to varying degrees. (Figure created with
BioRender.com).
exacerbated by decreased physical activity related to
being unwell. ‘Disseminated activated coagulation’ is
loosely applied as a descriptor, however, this term is
largely a misnomer as the presence of significant
microthrombi is not generally identified, either on
histological examination of failed organs [32] or
during interrogation of the microcirculation [16].
The rise in lactate seen in sepsis is also commonly
wrongly ascribed to be solely related to anaerobic
metabolism consequent to tissue hypoxia [33].
Although tissue hypoxia may exist to some degree,
at least in the early unresuscitated period, multiple
other causes for hyperlactatemia exist, including
liver dysfunction, mitochondrial dysfunction despite
adequate oxygen availability (see below), and cate-
cholamine-driven aerobic glycolysis with activation
of muscle sodium pumps that allow supply of
lactate to other organs as an energy substrate [34].
Septic shock is now recognized as a combination of
cardiovascular and cellular/metabolic abnormalities
represented by fluid-resistant hypotension and
hyperlactatemia [1].
BIOENERGETIC ALTERATIONS AND
METABOLIC SHUTDOWN – THE KEY TO
ORGAN DYSFUNCTION?
Paradoxically, cell death is relatively minor in
affected organs and not sufficient to explain the
degree of organ dysfunction seen in sepsis [32,35].
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Pathophysiology of sepsis Arina and Singer
Furthermore, in recovering patients, organs usually
recover within days to weeks, even those organs
with poor regenerative capacity such as the kidney.
Further erroneous misnomers are bandied around,
such as ‘acute tubular necrosis’ as the pathology
underlying acute kidney injury. Even at postmor-
tem, minimal if any necrotic tubules are seen within
the kidney in the vast majority of cases [32]. An
alternative hypothesis thus has to be sought to
explain functional abnormality in the absence of
significant structural damage.
We and others have advanced the view that
mitochondrial dysfunction leading to an insuffi-
ciency of energy substrate (adenosine triphosphate,
ATP) plays a major role [35,36]. Mitochondria
are present in every cell line except erythrocytes
that rely solely upon glycolysis for ATP production.
Compared to glycolysis, mitochondria generate sig-
nificantly greater amounts of ATP, predominantly via
the electron transport chain and, to a lesser degree,
the Krebs’ cycle. Mitochondria also play many other
critical roles within the cell including production of
hormones, modulation of metabolism, and initiation
of cell death pathways. They are the major source
within the body of reactive oxygen species (ROS). In
health, ROS play an important signaling role, how-
ever in sepsis they are produced in significant excess,
both from mitochondria (within the electron trans-
port chain) and activated leukocytes (via NADPH
oxidase). If production overwhelms endogenous
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antioxidant defenses, ROS can inhibit enzymes –
including the electron transport chain – and cause
oxidative damage to proteins, lipids, and DNA [37].
In sepsis, mitochondria can be affected in varied
ways resulting in inadequate functioning of oxida-
tive phosphorylation and production of ATP to
fuel metabolism [35,36]. Other than suffering a
lack of oxygen and substrate though macro- and
micro-circulatory disturbances, and direct effects of
inflammatory mediators, mitochondrial function
may be compromised by intrinsic damage related
to excessive ROS production, altered hormonal acti-
vation (e.g. the sick euthyroid syndrome as thyroid
hormone largely modulates metabolism via mito-
chondrial activation), and decreased gene transcrip-
tion of mitochondrial proteins. Even though cell
death is unusual in sepsis [32], changes in mitochon-
drial morphology are apparent [38]. Mitophagy, the
clearance of damaged mitochondria, is also affected
during sepsis [39].
Although glycolysis can be up-regulated to a
limited degree to generate more ATP, this would
not be sufficient in itself to maintain cellular metab-
olism. Continued metabolism would lead to a drop in
cellular ATP levels which, beyond a certain threshold,
would trigger apoptotic or even necrotic cell death
pathways. As the cell is generally intent upon sur-
vival, it has to adopt a more extreme approach to
survive by reducing its metabolic activity, sacrificing
many of its functional roles whereas focusing on life-
support tasks such as maintenance of membrane
integrity. At an organ level this is manifest as physio-
logical and/or biochemical dysfunction yet may actu-
ally represent an adaptive mechanism analogous to
hibernation or estivation where cells shut down in
the face of prolonged stress and resurface once more
normal conditions prevail [40]. Indeed, survivors of
sepsis show better preservation of ATP, a lesser degree
of mitochondrial dysfunction and a greater biogene-
sis signal compared to eventual nonsurvivors [38].
Recovery of organ function is thus contingent upon
restitution of an adequate energy supply to fuel
metabolism. This, in turn, requires restoration of
functioning mitochondria through enhanced bio-
genesis and mitophagy.
Metabolism is altered in sepsis, both temporally
and in terms of substrate utilization. Oxygen con-
sumption studies in patients show increases in the
early phase of sepsis followed by progressive down-
regulation in line with increasing illness severity,
and then a rebound increase during the recovery
phase as patients recover, heal and mobilize [41].
Patients decrease food intake during critical illness
so there is a shift away from carbohydrate to protein
and fat metabolism, with substrate obtained
through ‘auto-cannibalization’ of adipose tissue
6 www.co-anesthesiology.com
and skeletal muscle. This is mediated by an increase
in levels of catabolic stress hormones such as corti-
sol, glucagon and catecholamines whereas levels of
anabolic hormones such as insulin and growth hor-
mone, or their receptors, are downregulated. There
is increasing recognition that alterations in circulat-
ing metabolites and utilization, in particular of fatty
acids, modulate the inflammatory response [42].
FLUCTUATING HORMONAL INFLUENCES
IN SEPSIS
Hormonal production during sepsis is markedly
affected and influences multiple systems including
cardiovascular, immune, bioenergetic and meta-
bolic. The magnitude of change in hormone levels
is greater in eventual nonsurvivors, reflecting either
the severity of disease or possibly as a direct conse-
quence. Catecholamine levels are markedly elevated
for a prolonged duration, more so in eventual non-
survivors [43]. An initial increase in cortisol levels is
often followed by decreased production and cortico-
steroid insufficiency [44]. Thyroid hormone produc-
tion is reduced both centrally and/or peripherally,
with resulting low circulating levels of triiodothyro-
nine (T3) plus increased levels of inactive rT3 (reverse
T3) with consequent effects on bioenergetics and
metabolism [45]. Sex hormones – which have
immune- and inflammation-modulating activities
– also change precipitously in sepsis [46]. After a
transient early rise, vasopressin levels are not elevated
in sepsis, even in shock states; this relates to decreased
hypothalamic production and/or increased break-
down by vasopressinases [47]. The changes are com-
plicated further by alterations in hormone receptor
activity and/or density, or downstream pathways,
resulting in either decreased or increased responsive-
ness to their specific hormones. Examples include
insulin resistance leading to hyperglycemia [48],
vascular hyporeactivity to catecholamines [30], and
vasopressin hypersensitivity [47].
IMMUNOSUPPRESSION – PREDISPOSING
THE HOST TO A SECOND HIT
After the initial pro-inflammatory mediator excess
there is a shift toward an overall anti-inflammatory
milieu. Not necessarily concurrent, there is also a
decrease in immune functionality (e.g. decreased
phagocytic capacity, low HLA-DR density on mono-
cytes, decreased neutrophil chemotaxis) plus
increased apoptosis of lymphocytes and decreased
immunoglobulin production [49,50]. The net effect
is to place the septic patient at risk of secondary
infection, often with opportunistic organisms.
Immunosuppression can last for months after the
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septic event and may be an important factor under-
lying late deaths.
CONCLUSION
As described above, a highly complex series of events
occur in sepsis, likely involving each and every sys-
tem within the body, and can swing wildly during the
course of the illness. Pathways are either up- or down-
regulated. To what extent these changes are adaptive
or maladaptive must remain speculative at present
but is an important point to address as a well meaning
targeted intervention may be misguided and detri-
mental. Nonsurvivors generally follow a similar
though more extreme pattern to eventual survivors,
suggesting the need for cautious therapeutic modu-
lation rather than aggressive blockade or stimulation.
Many other aspects of sepsis pathophysiology have
not been discussed here but their relevance to the
disease process needs to be ascertained. Examples
include neural control mechanisms, organ-organ
cross-talk, metagenomics, the role of the microbiome
in the gut and other organs, epithelial dysfunction,
perturbation of other intracellular organelles such as
the endoplasmic reticulum, and the impact – posi-
tive and negative – of the multiple iatrogenic inter-
ventions inflicted on the patient.
Acknowledgements
None.
Financial support and sponsorship
Medical Research Council, Wellcome Trust, UK National
Institute of Healthcare Research, European Commission.
Conflicts of interest
There are no conflicts of interest.
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