critical care
Sepsis: A New Hypothesis for
Pathogenesis of the Disease Process*
Roger C. Bone, MD, PhD (honorary), Master FCCP;' Charles]. Grodzin, MD;
and Robert A Balk, MD, FCCP
(CHEST 1997; 112:235-43)
Abbreviations: CARS =compensatory anti-inflammatory re-
sponse syndrome; IFN =interferon; IL=interleukin; MARS=
mixed antagonists response syndrome; MODS=multiple organ
dysfunction syndrome; SIRS=systemic inflammatory response
syndrome; TNF=tumor necrosis factor
SThe
epsis is the systemic response to severe infection.
incidence of sepsis continues to increase.
Sepsis and its sequelae are the leading causes of
death in medical and surgical ICUs. 1 •2 According to
the Centers for Disease Control and Prevention, the
incidence of sepsis continues to increase and is now
the third leading cause of infectious death (Fig 1).
Sepsis and its sequelae represent progressive
stages of the same illness-a systemic response to
infection mediated via macrophage-derived cyto-
kines that target end-organ receptors in response to
injury or infection. Much confusion has existed
regarding terminology for sepsis. An American Col-
lege of Chest Physicians/Society of Critical Care
Medicine Consensus Conference 3 held in 1991
agreed to a new set of definitions that could be
readily applied to patients in different stages of
sepsis (Table 1). New discoveries made in the last
several years have validated the conceptual appro-
priateness of these terms, which has led to wide
acceptance. However, new discoveries also suggest
that we need to push these concepts further.
The pathophysiologic state of the systemic inflam-
matory response syndrome (SIRS) has been studied
extensively. We characterize SIRS as an abnormal
generalized inflammatory reaction in organs remote
from the initial insult. When the process is due to an
infection, the terms sepsis and SIRS are synony-
mous. On the basis of the current understanding of
*From the Department of Internal Medicine, Sections of Pulmo-
nary and Critical Care Medicine, Rush-Presbyterian-St. Luke's
Medical Center, Rush Medical College, Chicago.
1
Deceased.
Manuscript received April 28, 1997; accepted April 29.
sepsis and its sequelae, innovative therapies were
developed and clinical trials were begun. Although
these trials were of the most advanced experimental
design, double-blind, randomized, and placebo con-
trolled, all such sepsis trials thus far have failed to
show efficacy or have had harmful, ambiguous, or
negative results. 4 Pharmacologic interventions to
date have not improved the outcome in sepsis and
SIRS. The trials have shown how effective certain
agents can be at the cellular or animal model stage
but how ineffective these same agents can be when
applied in clinical trials. 4
While trials addressed the proinflammatory phase
of sepsis and SIRS, there was no evidence that the
proinflammatory phase was dominant when drugs
were given. This may mean more to us as we learn
more about compensatory anti-inflammatory re-
sponses and mixed proinflammatory and anti-inflam-
matory responses in the human with sepsis. The
failed initial clinical trials tested efficacy of clinical
trials for sepsis and provided some insight into the
complexity of the immuno-inflammatory cascade.
This article looks at what we know about this com-
plex immuno-inflammatory cascade, and a new hy-
pothesis to relate it to sepsis.
SEPSIS, SIRS, CARS, AND MARS
When the American College of Chest Physicians
and Society of Critical Care Medicine convened a
Consensus Conference in 1991 to address the prob-
lem of confusion over use of proper terms and
definitions, the terms bacteremia, septicemia, sepsis,
sepsis syndrome, and septic shock were being used
almost interchangeably, which led to confusion and
imprecise understanding of sepsis and related disor-
ders. Members of the Consensus Conference agreed
to a new set of definitions that could be readily
applied to patients in different stages of sepsis:
bacteremia, SIRS, sepsis, severe sepsis, septic shock,
and multiple organ dysfunction syndrome (MODS).
CHEST/112/1 /JULY, 1997 235
 30
25
0 • 1980
0
0 20
--
0
0
,... 15
( /)
.r::: 10
m
(1)
0 5
0
Lung AIDS Sepsis
FIGURE l. Leading causes o f infectious death according to ll, c Centers for Disease Control and
Prevention .
We propose now to add the compensatory anti-
inflammatmy response syndrome (CARS ), and
mixed antagonists response syndrome (MARS ) to
this set of clinical deflnitions (Table 2).
Multiple organ d ysfunction occurs in about 30% of
patients with sepsis, and it also can be found in
trauma patients, patients with acute pancreatitis and
othe r diseases such as systemic vasculitides, and in
burn victims. 5 · 9 How dysfunction of multiple organs
can be produced by such disparate disorders puzzled
clinicians and investigators for years. Almost a d e-
cade ago, it was suggested that multiple organ
dysfunction may result not from infection per se, but
from a generalized inflammatory reaction.l 0 Evi-
dence today suggests that a massive inflammatory
reaction resulting from systemic cytokine release is
the common pathway underlying multiple organ
dysfunction. Also, it is now known th at most patients
have evidence of dysfunction in one or more organs
long before organ failure develops.
Unfortunately, th e more we learn about this in-
flamm atory response, th e more difficult it becomes
to pinpoint a speciflc cytokine, or a specific reaction,
as the "cause" of SIRS . Indeed, it has become clear
that cytokine release i s a normal, healt hy part of the
body's r esponse to insult or infection. Cytokines are
highly pleiotropic, and they appear capable of pro-
ducing markedly different effects depending on the
nearby hormonal milieu. Fmthennore, the body has
a highly complex, rigidly regulated n etwork of recep-
tor antagonists and other r egulatory agents that
continuously modulate the effects of cytokine re-
lease . Adding to our confusion is the fact that
systemic cytokin e release can occur in a variety of
disorders without leading to organ dysfunction. Even
236
D 1992
Urinary Heart Hepato TB
tract biliary
in those disorders that are often associated with
organ dysfunction, the pattern of systemic cytokine
release is dissimilar. How, then, can SIRS and
MODS be explained ?
THE CYTOKINE CASCADE
The systemic response to infection is mediated via
the macrophage-derived cytokines that target end-
organ receptors in response to injury or infection.
The inflammatory response to infection or injury is a
highly conserved and regulated reaction of the or-
ganism . After recognition that a response is required,
the organism (eg, a human being) produces soluble
protein and lipid proinflammatmy molecules that
activate cellular defenses, then produces similar
anti-inflammatoty molecules to attenuate and halt
the proinflamm atmy response. Molecules known or
presumed at this time to be proinflammatory and
anti-inflammatory are listed in Table 3. Presumption
of activity is basedon data of varyi ng qu ality; it is
likely that some molecules will eventu ally drop from
this list, and others will be added.
Normally cytokine response is regulated b y the
intricate nel:\vork of proinflamm atory and anti-in-
flamm atmy mediators. The initial inflammatory re-
sponse is kept in check b y down-regulating produc-
tion and counteracting the effects of cytokines
already produced. The picture that emerges from
analysis of data from patients with sepsis is that a
complex mixture of proinflammatory and anti-in-
flammatory molecules may be present.11 · 12 Standard
pathophysiologic models of sepsis do not explain
such a picture.l3
Critical Care
 Table !-Standard Definitions for Sepsis and Organ
Failure
Terminology Definition
Infection Microbial phenomenon characterized by a n
inflammatory response to the presence of
microorganisms or the invasion of normally
sterile host tissue by those organisms.
Bacteremia Presence of viable bacteria in the blood.
SIRS The systemic inflammatory response to a \vide
variety of severe clinical insults, manifested by
two or more of the following conditions: (1)
temperature >38°C or <36°C; (2) heart rate
>90 beats/min; (3) respiratory rate >20
breaths/min or PaC0 2 <32 mm Hg; and (4)
WBC count > 12,000/mm 3 , <4,000/mm 3 , or
> 10% immature (band ) form s.
Sepsis The systemic inflammatory response to infection.
In association with infection, manifestations of
sepsis are the same as those previously defined
for SIRS. It should be determined whether
they are a part of the direct systemic response
to the presence of an infectious process and
represent an acute alteration from baseline in
th e absence of other known causes for such
abnormalities.
Severe sepsis Sepsis associated with organ dysfunction,
hypoperfusion, or hypotension. Hypoperfusion
and perfusion abnormalities may include, but
are not limited to, lactic acidosis, oligUiia, or an
acute alteration in mental status.
Septic shock A subset of severe sepsis and defined as sepsis-
induced hypotension despite adequate fluid
resuscitation along with the presence of
perfusion abnormaliti es that may include, but
are not limited to, lactic acidosis, oligUiia, or an
acute alteration in mental status. Patients
receiving inotropic or vasopressor agents may
no longer b e hypotensive by the time they
manifest hypoperfusion abnormalities or organ
dysfunction, yet they would still be considered
to have septic shock.
MODS Presence of altered organ function in an acutely
ill patient such that homeostasis cannot be
maintained without intervention.
Sepsis-induced A systolic BP <90 mm Hg or a reduction of ~40
hypotension mm Hg from baseline in the absence of other
causes for hypotension.
These mediators initiate overlapping processes
that directly influence the endothelium, cardiovascu-
lar, hemodynamic, and coagulation mechanisms. The
release of many of these vasoregulators is often local.
Evolving concepts of the septic response give more
weight to the importance of local cytokine produc-
tion, not in contradistinction to systemic production
but as part of the total septic-response picture. 4 · 14
The duration of illness also may alter the mix of
mediators, leading to a state of metabolic disorders
in which the body has no control over its own
inflammatory response. If balance cannot be estab-
lished and homeostasis is not restored, a massive
Table 2-Proposed Definitions for Sepsis and Organ
Failure
CARS HLA-DR on monocytes <30% and diminished
ability of monocytes to produce inflam matory
cytokines, such as TNF-a or IL-6 (Kox WJ, Bone
RC , Krausch D, et a!. Arch Intern Mecl 1997; 157:
.389-93).
MARS Features of SIRS in a patient with CARS.
proinflammatory reaction (SIRS) or a compensatory
anti-inflammatory reaction (CARS) will ensue. A
range of clinical sequelae may then follow. These
sequelae can be remembered by using the mne-
monic CHAOS (Fig 2) .
Currently, our concept of the pathogenesis of
sepsis is undergoing evolution, based in part on
animal models or human exposure to endotoxin, in
hopes of finding a "magic bullet" for sepsis. 4 The
magic bullet to definitively treat sepsis has been
vigorously sought, but has not been found. More
than a dozen pharmacologic magic bullet candidates
have failed to improve outcome of sepsis in random-
ized, placebo-controlled clinical trials . Magic bullet
trials were based on an assumption that antagonism
of a single proinflammatory mediator can modulate
the cascade of events that constitutes sepsis in a
heterogeneous group of patients. Hindsight indicates
that this was simplistic, but evidence available at that
time was interpreted to suggest that such a strategy
should be successful. Similarly, available evidence
suggested that neutralization of endotoxin would
prevent the proinflammatory response, but clinical
trials of monoclonal antiendotoxin antibodies were
not successful. 15 - 18 The design of clinical trials man-
dated that patients enrolled in the trial meet some
criteria for having sepsis, ignoring any preexisting
condition that might have induced proinflammatory
mediators. 19 Animal studies suggested that an endo-
toxin-neutralizing drug should be given before or
shortly after the inflammatory stimulus, but interspe-
cies variation in immunomodulation and other dif-
ferences in animal models compared to the critically
ill ICU patient make it difficult to generalize animal
studies to humans. 2 o
WHY PREVIOUS THEORIES WERE INADEQUATE
We have understood that a massive inflammatory
reaction underlies both SIRS and MODS, but now
we must understand that this reaction is only half the
picture. It is now clear that quite rapidly after the
first proinflammatory mediators are released, the
body mounts a compensatory anti-inflammatory re-
action (CARS) to the initial proinflammatory re-
CHEST /112/1 I JULY, 1997 237
 Table 3-Partial List of Proinflammatory and Anti-inflammatory Molecules
l'roinflammatory Molecules Anti-inflammat01y Molecules
TN F-a Thromboxane IL-l ra
IL-113 Platelet activatin g factor IL-4
IL-2 Soluble adhesion molecules IL-10
IL-6 Vasoactive neuropeptides IL-13
IL-8 Phospholipase A2 Type II I L-1 receptor
IL-15 Tyrosine kinase Transforming growth factor-13
Neutrophil elastase Plas minogen activator inhibitor- I Epinephrine
IFN--y Free radical generation Soluble TNF-a receptors
Protein kinase Neopterin Leukotriene B4 -receptor antagon ism
MCP-1* CD14 Soluble re combinant CD-14
MCP-2 Prostacyclin LPS binding protein*
Leukemia inhibitory factor Prostaglandins
(D-factor)
*MCP = monocyte chemoattractant protein; LPS = Iipopolysaccharide.

sponseP The anti-inflammatory reaction may be as
large as, and sometimes even larger than, the proin-
flammatory response. The goal of this anti-inflam-
matmy reaction is to down-regulate synthesis of
proinflammatory mediators and to modulate their
effects, thereby restoring homeostasis.
It has recently become possible to differentiate
ongoing CARS from SIRS immunophysiology.
Zedler et al21 detailed a technique of stimulating
peripheral blood mononuclear cells from severely
injured burn patients for the purpose of cell surface
antigen staining and intracellular interferon-gamma
(IFN-)') and interleukin-4 (IL-4) detection. IL-4, an
anti-inflammatory cytokine, was found in excess (el-
evated 16-fold) in the presence of downregulated
IL-2 and IFN-)'. IL-4 thus served as a marker for the
"THrTH 2 switch," a major characteristic of the
CARS response to injury (THis the T h elper cell) . In
most healthy persons, the body is able to achieve a
balance between proinflammatory and anti-inflam-
C Cardiovascular compromise (usually manifesting
as shock; in this setting SIRS predominates).
H Homeostasis (return to health; this represents a
balance of SIRS and CARS).
A Apoptosis (neither SIRS nor CARS predominates).
0 Organ dysfunction (single or multiple;
SIRS predominates).
S Suppression of the immune system (anergy and/or
increased susceptibility to infection ; CARS
predominates) .
FIGURE 2. Mnemonic of CHAOS.
matory mediators and homeostasis is restored (Fig
2) . In some patients, however, a variety of forces
conspire to upset this balance, resulting in SIRS and
MODS.
The theories put forth to explain the development
of SIRS have generally not taken this compensatory
anti-inflammatOI)' reaction into consideration. Many
of the anti-inflammatory mediators were discovered
and characterized only in the last few years, and to
some extent, this may have led to overstatement of
the dangers presented by proinflammatory media-
tors . It might almost be said that proinflammatmy
mediators became "bad guys ," without taking into
account that excessive levels can be harmful, but
lower levels are required to combat pathogenic
organisms and to promote healing.
Most of the evidence for the role of proinflamma-
tory mediators in the pathogenesis of SIRS and
MODS came from studies using animal models,
experiments in which endotoxin or proinflammatory
mediators were injected into human volunteers, and
analysis of serum levels of proinflammato1y media-
tors in patients \Vith sepsis, burn injury, or other
severe injuries (Fig 3) . We now know that these
studies may not truly reflect what happens in criti-
cally ill patients with sepsis or SIRS. As noted earlier,
a marked interspecies variation in cytokine release
makes it difficult to extrapolate results of animal
studies to humans. More importantly, these experi-
ments were performed on healthy animals and gen-
erally included a relatively short observation peri-
od.22 Studies of human volunteers were performed
in healthy subjects; the amount of stimulus injected
was sublethal; and, again, the follow-up period was
brief. 23 In contrast, SIRS and MODS develop over
time in severely ill or injured patients who have
multiple preexisting disorders.24
Serum levels of immunomodulating mediators

238 Critical Care

 result of an immediate insult such as trauma and not
a consequence of a preexisting condition such as
Infection pancreatitis.19

'
RELATING CLINICAL RESPONSES TO CYTOKINE
CASCADE

Endotoxin and Some patients with sepsis, extensive burns, mas-

sive traumatic injury, or other severe insults show
other microbial toxins little or no evidence of a systemic inflammatory
reaction or organ dysfunction, although their recov-

'
ery may be protracted because of the severity of their
underlying illness. In three other categories, how-
ever, are patients with sepsis or other severe insult
who develop the following: a mild form of SIRS and
Proinflammatory state some evidence of dysfunction in one or two organs
with cytokine release early in their clinical course that usually resolves
rapidly; a massive systemic inflammatory reaction
and developing rapidly after the initial insult, with death
other proinflammatory often following within a few days from profound
shock; and a less severe initial course, but marked
mediators deterioration several days or more after the original
insult, with outright failure of one or more organs

'
and death in some but not all patients.
Clinical trials have usually excluded patients with
mild symptoms of organ dysfunction or symptoms
that last for <24 or 48 h. While this was perhaps
Sepsis/SIRS believed necessary to the design and conduct of
these trials, the underlying hypothesis may have

'
been faulty. We should have looked better at the
proinflammatory and anti-inflammatory response to
severe insult and asked whether the inflammatory
response was of an appropriate magnitude and if it
Shock and multiorgan was appropriately down-regulated. When down-reg-
dysfunction and ulation is not adequate, is there a progression of
severities? Rangel-Frausto et al 28 published the first
possible large study to confirm that patients progress through
death stages of the septic process, from mild to severe.

FIGURE 3. Old paradigm for sepsis.
present problems of interpretation because immu-
noassays can detect only free, circulating mediators,
not mediators bound to cells or receptors. 12,2.5,26
Therefore, the amount of mediator reported may not
be the amount present. Bioassays used to measure
the functional activity of cytokine often lack speci-
ficity and may over-report the amount of mediator
present. 27 Other points to consider are the following:
( l) analysis of serum level is usually performed once
a day or less often, although mediator release is
phasic; and (2) most analyses have assumed that the
presence of proinflammatory mediators is a direct
A NEW THEORY OF SIRS, CARS, MARS, AND
MODS
Immunomodulation is a complex, overlapping net-
work of interactions among agents that work to-
gether to overcome severe assaults on the body.
Paradoxically, they also work to the body's disadvan-
tage and cause the disruptions we call SIRS and
MODS. We have presented a hypothesis-based ex-
planation for the apparently paradoxical events ob-
served in the ctitically ill (Fig 4). The five stages in
the development of multiple organ dysfunction are
as follows: (1) local reaction at the site of injury or
infection; (2) initial systemic response; (3) massive
systemic inflammation; (4) excessive immunosup-
pression; and (5) immunologic dissonance. 29

CHEST I 112 I 1 I JULY, 1997 239

 In itial insult
(bacterial,
viral, traumatic,
thennal)

A 0 s
Cardiovascular Hom eo- Apoptosis Organ Suppression
compromise stasis (cell death) dysfunction of the
(shock) immune
system

SIRS CARS and Death w~h SIRS CARS

predominates SIRS minimal predominates predominates
balanced inflammation

FIGURE 4. New concepts for the clinical sequelae of sepsis, SIRS , CARS, and MARS . (This figure is
an adaptation of Figure 1by Bone RC. Sir Isaac Newton, sepsis, SIRS, and CAH.S. Crit Care Med 1996;
24:1125-28.)

Stage 1 substances 12 •30 -32 work to diminish monocytic major

Prior to development of SIRS or MODS is some
insult such as a nidus of infection, a traumatic injury
(including a surgical wound), a burn injury, or
pancreatitis that prompts release of a variety of
mediators in the microenvironment. The body's ini-
tial response is to induce a proinflammatory state in
which mediators have multiple overlapping effects
designed to limit new damage and to ameliorate
whatever damage has already occurred. They destroy
damaged tissue, promote the growth of new tissue,
and combat pathogenic organisms, neoplastic cells,
and foreign antigens 2 0 ·24 (Table 3).
A compensatory anti-inflammatory response soon
ensures that the effects of these proinflammatory
mediators do not become destructive. IL-4, IL-10,
lL-11, IL-13, soluble tumor necrosis factor (TNF-a)
receptors, IL-l receptor antagonists, transforming
growth factor-[3 , and other, as yet undiscovered
histocompatibility complex class II expression, im-
pair antigen presenting activity, and reduce the
ability of cells to produce inflammatory cytokines.
Local levels of both proinflammatory and anti-in-
flammatory mediators can be substantially higher
than are later found syste mically33 -38 (Table 3).
Stage 2
If the original insult is sufficiently severe, first
proinflammatory and later anti -inflammatory media-
tors will appear in the systemic circulation via a
variety of mechanisms. The presence of proinflam-
matOiy mediators in the circulation is part of the
normal response to infection and serves as a warning
signal that the microenvironment cannot control the
initiating insult. The proinflammatory mediators
help recruit neutrophils, T cells and B cells, platelets,
and coagulation factors to the site of injury or

240 Critical Care

infection. 24 This cascade stimulates a compensatory
systemic anti-inflammatmy response, which nor-
mally quicldy down-regulates the initial proinflam-
matory response. Few, if any, significant clinical
signs and symptoms are produced. Organs may be
affected by the inflammatory cascade, but significant
organ dysfunction is rare.
Stage 3
Loss of regulation of the proinflammatory re-
sponse results in a massive systemic reaction mani-
fest as the clinical findings of SIRS. Underlying the
clinical findings are pathophysiologic changes that
include the following: (1) progressive endothelial
dysfunction, leading to increased microvascular per-
meability;39-43 (2) platelet sludging that blocks the
microcirculation, 44 causing maldistribution of blood
flow and possibly ischemia, which in turn may cause
reperfusion injmy5 and induction of heat shock
proteins;46 (3) activation of the coagulation system
and impairment of the protein C-protein S inhibitory
pathway;47 and (4) profound vasodilation, fluid tran-
sudation, and maldistiibution of blood flow may
result in profound shock. 48 ·49 Organ dysfunction and,
ultimately, failure result from these changes unless
homeostasis is quickly restored.
Stage 4
It is possible that a compensatmy anti-inflamma-
tory reaction can be inappropriate, with a resulting
immunosuppression. What some investigators have
called "immune paralysis,"50·51 and "window of im-
munodeficiency,"·52 we describe as "compensatory
anti-inflammatory response syndrome" (CARS). 4
CARS is the body's response to inflammation and is
more than just immune-paralysis. CARS may explain
such anomalies as the burn patient's increased sus-
ceptibility to infection and even the anergy of the
pancreatitis patient. 29 ·53 Recently, it has been shown
that treatment of patients with sepsis with IFN--y not
only restores the HLA-DR expression on monocytes
but reestablishes the ability of monocytes to secrete
the cytokines IL-6 and TNF-a. 29 One recent study55
looked at a series of patients admitted to an ICU who
met the criteria for SIRS. All patients demonstrated
CARS immunophysiology in that monocyte surface
human leukocyte antigen (HLA)-DR expression was
reduced to < 30%. The study confirmed that admin-
istration of IFN--y-1b could effect up-regulation of
monocyte surface HLA-DR expression, restoration
of monocyte function , and secretion of IL-6 and
TNF -a. The resultant state rebalances CARS-SIRS
immunophysiologic homeostasis.
Stage 5
The final stage of MODS is what we have elected
to call "immunologic dissonance."54 It is an inappro-
priate, out-of-balance response of the immunomodu-
latory system. In some patients, it results from
persistent, overwhelming inflammation that may
persist in patients with SIRS and MODS, with
increased risk of death.u,.ss-.57
In some patients, persistent immune suppression
causes immunologic dissonance. Studies have shown
not only that monocyte deactivation persists in many
patients, but that such persistent deactivation greatly
increases the risk of death.51 In patients with persis-
tent immune suppression, the cause of organ failure
may be inhibition of the· synthesis of the proinflam-
matory agents needed to allow the organs to recover.
In patients with immunologic dissonance, it may be
possible to regain organ function if the body can
recover its balance.
CONCLUSIONS
Balance between proinflammatory and anti-in-
flammatmy forces could conceivably be lost: ( 1)
when infection, burn injury, hemorrhage, etc, is so
severe that the insult alone is sufficient to prompt
SIRS and MODS; or (2) when patients are "pre-
primed" to develop SIRS and MODS by preexisting
severe illness. (3) Most of the preexisting conditions
are associated with abnormal cytokine levels. 19
The hypothesis of prepriming rests on our under-
standing that a patient at risk for SIRS or MODS
already has a significant clinical history, and is not
clinically analogous to a healthy human volunteer.
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