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Centennial Review

Pathobiology of Sepsis
Are We Still Asking the Same Questions?
Rebecca M. Baron, Miriam J. Baron, and Mark A. Perrella
Division of Pulmonary and Critical Care Medicine, Division of Infectious Diseases and Channing Laboratory; and Department of Medicine,
Brigham and Womens Hospital, Boston Massachusetts
While the term sepsis has been used for centuries to describe
critical illness resulting from infection, a specic denition and
conceptual basis for its genesis are still debated (13). Despite
incredible clinical technological advances and molecular prog-
ress in dening the pathobiology of bacterial infection, the inci-
dence of sepsis and associated mortality remain exceedingly
high (4). To date, with the exception of activated protein C,
no recently developed specic therapies for sepsis have proven
effective, despite numerous clinical trials (5). Failures of these
trials, many of which targeted identied mediators of the in-
ammatory cascade, led to cries for reinvestigation of basic dis-
ease mechanisms (3, 6). In fact, recent studies have elicited
exciting new answers to very old questions, which suggest novel
avenues of investigation and future treatment strategies for sep-
sis. In this review, we set out to explore how our understanding
of the pathobiology of sepsis has evolved, through examining
historically how investigators have tried to answer four basic
mechanistic questions:
1. What is sepsis?
2. How do we identify the bacterial pathogen?
3. Is there a critical toxic factor in sepsis?
4. What role does the host response play in sepsis?
What Is Sepsis?
Sepsis as Rottenness: Theory of Spontaneous Generation
The concept of sepsis dates at least as far back as the time of
Hippocrates and was viewed as a process of dangerous, odorous
biologic decay, or putrefaction (7). Ancient Greeks believed this
process was one form of biologic breakdown that could occur
within the body and, furthermore, that there existed dangerous
principles within the colon that were capable of causing autoin-
toxication. Aristotle, and later the Romans, proposed that
within swamps, the process of sepsis resulted in the production
of invisible living creatures that emanated inputrid fumes termed
miasmata (Figures 1 and 2). Thus persisted for centuries the
concept of spontaneous generation of tiny dangerous animals,
and early public health initiatives in Roman cities were directed
toward elimination of these perceived deadly swamps.
(Received in final form December 13, 2005)
Correspondence and requests for reprints should be addressed to Rebecca M. Baron,
M.D., Division of Pulmonary and Critical Care Medicine, Brigham and Womens
Hospital, 75 Francis Street, Boston, MA 02115. E-mail: rbaron@partners.org
Am J Respir Cell Mol Biol Vol 34. pp 129134, 2006
DOI: 10.1165/rcmb.F308
Internet address: www.atsjournals.org
Only in 1684 did a controlled experiment begin to refute
the concept of spontaneous generation. Francisco Redi baited
three pots with meat, which was allowed to age under the
following conditions (8):
(1) Meat, open to the air.
(2) Meat, open to the air, but pot covered with mesh gauze.
(3) Meat, covered with airtight seal.
In the rst condition, ies ew in and out of the pot freely,
and the meat was ooded with maggots shortly thereafter. In
the second condition, maggots were seen only upon the gauze,
not in contact with the meat. In the third condition, the meat
in the airtight container was free of maggots. Redi concluded
that rather than generating the insects, rotten meat attracted
the ies to lay the eggs that produced the maggots. While this
experiment was compelling, the contemporaneous development
of the microscope conrmed the presence of simple tiny ani-
mals, leading to the revival of spontaneous generation as an
explanatory model for sepsisa model that persisted for nearly
200 years more.
Sepsis as a Result of Infection: Development of
The Germ Theory of Disease
Ignaz Semmelweiss noted in 1841 that women in his maternity
ward in Vienna who were cared for by midwives suffered a
signicantly lower rate of death from childbed (puerperal) fever
(2%) than did those cared for by physicians (16%) (9). Physicians
performed autopsies on the women who had died the previous
day, while the midwives did not. When one of his colleagues
died after sustaining a laceration during an autopsy, Semmelweiss
wrote:
Suddenly a thought crossed my mind: childbed fever and the death
of Professor Kolletschka were one and the same. His sepsis and
childbed fever must originate from the same sourcethe ngers and
hands of students and doctors, soiled by recent dissections, carry
those death-dealing cadavers poisons into the genital organs of women
in childbirth.
Semmelweiss instituted handwashing precautions before pa-
tient contact, and this intervention resulted in a reduction in the
overall mortality rate from 18% to less than 3% in his maternity
ward. However, his results were not well received by the medical
community, as reected in this statement from an American
obstetrician: Doctors are gentlemen, and gentlemens hands
are clean. Semmelweiss was red from his position. He later
died in an insane asylumironically, from an illness resembling
puerperal sepsis, incurred from a nger laceration (9).
An elegant experiment in 1859 by Louis Pasteur nally dis-
proved spontaneous generation. He allowed boiled broth to
stand in asks that had curved swan necks, such that microbes
from the air could settle on the necks of the ask, but broth
could contact the microbes only if the ask was tipped to bring
130 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL 34 2006
Figure 1. Methods of identifying bacterial
pathogens, from prenineteenth century
tothe present time. (A) Adrawingby Louis
Joblot in 1718 of small animals (animal-
cules) seen under the microscope. The
appearance is reminiscent of protozoa (in-
cluding one with a human face). Adapted
from Reference 14. (B) Culture plate with
bacterial growth and Grams stain of bac-
teria. (C) Schema of 16S ribosomal DNA
bacterial sequencing from bacterial cul-
ture or from patient sample.
broth into the neck of the ask. In this famous experiment, he
found that sterile broth not in contact with microbes exhibited
no bacterial growth when allowed to sit for prolonged periods,
while sterile broth that contacted microbes on the neck of the
ask always turned cloudy. Thus, Pasteur conclusively demon-
strated that the process of putrefaction required living organisms
(8). Furthermore, in the 1870s, Robert Koch, a country physician,
showed that a particular microbe was the etiologic agent of
anthrax, a reproducible clinical syndrome that was aficting large
numbers of farmers and livestock in his community. Koch later
described the etiologic agents of a number of other diseases,
Figure 2. Overview of sepsis pathways, as outlined from
prenineteenth century to the present time.
including cholera and tuberculosis, and received a Nobel prize
in recognition of these achievements 100 years ago (10). His
work, in conjunction with Pasteurs ndings, established the
germ theory of disease, nally supplanting spontaneous
generation. Kochs postulates for microbial disease causation
established the eld of microbiology (8):
1. The suspected agent must be isolated from the diseased
victim.
2. The agent must be grown in pure culture.
3. Infection of a healthy host produces the classical disease.
4. The same organism must be isolated from the new victim.
Centennial Review 131
On the basis of these principles, Joseph Lister contemporane-
ously demonstrated the benecial effects of antiseptic techniques
(use of carbolic acid wound treatments), in signicantly reducing
perioperative mortality from limb amputation (11). His work,
along with the writings of Pasteur and Koch, ultimately ushered
in the conceptual notion of infection as causal in sepsis (7).
However, the scientic community was still slow to adapt, as he
writes:
during the previous nine months, in which the antiseptic system
had been fairly in operation in my wards, not a single case of pyaemia,
erysipelas, or hospital gangrene had occurred in them but the
carrying out of this rule implies a conviction of the truth of the germ
theory of putrefaction, which, unfortunately, is in this country the
subject of doubts such as I confess surprise me, considering the
character of the evidence which has been adduced in support of it.
The concept of sepsis as the systemic response to infection
has persisted, and remains dened as such to this day based
upon the deliberations of multidisciplinary consensus conferences
(1, 2) (Table 1). However, ongoing debate and discussion persist
in dening sepsis, as reected in proposed revisions to the 1992
consensus conference denitions, which will be discussed below
(2). Interestingly, the denitions of sepsis and related conditions
currently in use are remarkably similar to those put forth by
William Osler in The Principles and Practice of Medicine 100
years earlier (1, 12) (Table 1). Furthermore, Oslers proclama-
tion of the critical nature of source control in sepsis management
remains true to this day (12, 13): The brilliant and remarkable
results which follow complete evacuation of pus with thorough
drainage give the indication of the only successful treatment of
this condition.
How Do We Identify the Bacterial Pathogen?
Visualizing Bacteria
While is it now appreciated that infection and sepsis can arise
from nonbacterial pathogens, we have focused this historical
TABLE 1. DEFINITIONS OF SEPSIS AND RELATED CONDITIONS (1892, 1992); PROPOSED PIRO CLASSIFICATION SCHEME FOR
SEPSIS (ADAPTED FROM 2003 CONSENSUS PAPER [1])
Definitions: William Osler, 1892 (12) Definitions: Consensus, 1992 (2) Proposed Scheme: Consensus, 2003 (1)
1. Septicaemia Systemic Inflammatory Response (SIRS) Predisposition
(a) Fermentation fever 2 or more of following: Underlying illness
Fever, wound infection Temp 38C or 36C Genetics
Temp103104F Heart Rate 90 bpm Pathogenhost interaction
RR 20 or Pa
CO
2
32
WBC 12K, 4K or 10% bandemia
(b) Saepremia Sepsis: SIRS infection Insult infection
Septic intoxication, 24h Severe sepsis: sepsis with organ dysfunction, Culture pathogen
Temp 103104F hypoperfusion, or hypotension Source control
Quick pulse LPS, virulence factors
Delirium
(c) Progressive septicaemia Septic shock: sepsis with hypotension despite Response
Septic intoxication 2472 h fluid resuscitation SIRS, shock, CRP
Organisms in blood IL-6, TNF-, protein C levels
Fever, pulse 120 bpm
Delirium, apathy
2. Pyaemia Multiple organ dysfunction syndrome Organ dysfunction
Disseminated abscesses Altered organ function in an acutely ill patient; No. failing organs or composite score
Organisms in blood intervention required for homeostasis Apoptosis, cytopathic hypoxia, cell stress
Small vessel necrosis
Recurring chills, fever
Constitutional symptoms
Definition of abbreviations: bpm, beats per minute; RR, respiratory rate (in breaths/min); WBC, white blood cell count.
review on bacterial pathogens. As described above, even before
the development of the microscope and the ability to visualize
bacteria, ancient people imagined that there existed invisible
creatures, or small animals (animalcules) that were responsible
for dangerous diseases. Anton von Leeuwenhoek rst described
bacterial organisms (cocci, rods, and spirals) in 1674 using a
single-lens microscope, but a systematic study of bacteria was
not undertaken until nearly 100 years later. In fact, a drawing
of small animals (animalcules) made by Louis Joblot in 1718
suggests the appearance of protozoa (including one with a human
face) (Figure 1A) (7, 14). Thus resolution of commercially avail-
able lenses was likely not sufcient for uniform visualization of
bacteria at that time.
Culturing Bacteria
Microbiological techniques in the late 1800s improved the ability
to culture and identify bacteria through biochemical tests, and
similar techniques are still used to this day (Figure 1B). In devel-
oping methods for staining and identifying bacteria, Paul Ehrlich
laid the groundwork for the development of antibacterial ther-
apy (15). He hypothesized that if bacteria could take up dye
selectively, then it might be possible to develop a magic bullet
to kill bacteria but spare the surrounding cells. Approximately
thirty years later, in 1939, Gerhard Domagk was awarded a
Nobel Prize for demonstrating that a dye (protonsil red) adminis-
tered to mice with streptococcal infection was converted in vivo
to a sulfonamide with antibacterial properties. Development of
additional antibiotics followed, with the most famous resulting
from Alexander Flemings 1928 observation of inhibited cocci
growth on a culture plate in the vicinity of a mold (later identied
as Penicillium notatum, from which penicillin was isolated). Con-
centration, production, and clinical use of penicillin were put
forth by Howard Florey and Ernest Chain in 1941, and they
were awarded a Nobel Prize in 1945.
132 AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY VOL 34 2006
The acceptance of the germ theory, the successful applica-
tion of antiseptic techniques in the nineteenth century, and treat-
ment of infections with antibiotics in the twentieth century all
supported the concept that bacteria caused infections that were
detrimental to the host. However, several observations suggest
that there are still gaps in our understanding of the pathobiology
of sepsis. First, while early administration of appropriate antibi-
otics (within 1 h of presentation) improves sepsis outcomes and
remains a crucial part of the current standard of care (16, 17),
a signicant mortality rate persists in sepsis, despite treatments
targeting the microbe(s) identied in cultures (4). A number of
explanations have been proposed for this phenomenon, includ-
ing delay in appropriate antibiotic or resuscitative treatment
(17), increased virulence of the existing microbes (18, 19), or
exuberant uncontrollable host responses (which will be discussed
below). Second, cultures remain negative in 30% of patients
with sepsis. While negative cultures are often attributed to prior
use of antibiotics (4), it is possible, as was believed in earlier
times, that there still exist invisible bacteria contributing to
sepsis that evade current culture techniques.
Molecular Identification of Bacteria
With the development of molecular methods over the last twenty
years, it has become possible to identify bacteria through analysis
of their ribosomal RNA genes (rDNA). This approach yields
results, even if the species cannot be grown in culture (Figure
1C). With the use of this method, in fact, it has become increas-
ingly clear that the majority of existing microorganisms in the
environment cannot be cultured with standard techniques (20,
21). As a result, it has been proposed that Kochs postulates
be adjusted to reect the complicated gene-based techniques
employed to assign disease causation in the molecular era (22).
Recently, examination of rDNA sequences was undertaken
to identify vaginal bacterial species from patients with bacterial
vaginosis (BV), a disease in which causative organisms have not
been identiable in vaginal uid cultures (23). Instead, diagnosis
has been made traditionally on clinical grounds or with Grams
staining, and the condition has been poorly responsive to anti-
biotic treatment. Interestingly, the investigators found greater
diversity of bacterial species identied by 16S rDNA analysis of
vaginal uid from patients with BV than from control patients.
Furthermore, patients with BV were found to carry 16 novel
bacterial species not previously described, which were not iso-
lated from the control group patients. Further, uorescence
in situ hybridization demonstrated that these new bacterial
organisms resembled those often visualized by Grams staining
in vaginal uid of patients with BV. This association study does
not prove that these novel bacterial species cause BV, and BV
clearly represents a different clinical scenario from sepsis (24).
However, two small studies have explored use of rDNA analysis
in identifying causative bacterial pathogens in neonatal sepsis
(25). These studies raise the tantalizing possibility of rapid, in-
creasingly specic pathogen identication techniques in the fu-
ture that may dramatically improve our ability to identify patho-
gens against which to target antibacterial therapy.
Is There a Critical Toxic Factor in Sepsis?
The concept of a toxic factor in sepsis dates back to ancient
times, as described above, and has recurred in different concep-
tual phases throughout history. Herodotus reported that ancient
Egyptians used enemas three times per month to purge them-
selves of the dangerous toxic substances in the gastrointestinal
system (4).
In more recent times, physicians caring for wounded soldiers
during World War I recognizeda subset of patients withhypoten-
sion disproportionate to the extent of the blood loss. Further-
more, these patients were refractory to the standard resuscitation
measures used at the time (26). Animal models of hind-limb
injury studied by Walter Cannon and others in 19181920 sug-
gested that a toxic substance (histamine) was absorbed from the
injured muscle that propagated a shock-like state independent
of the extent of blood loss. However, improved animal models
and more advanced techniques applied by Alfred Blalock dis-
proved this concept in 1930, and he was able to attribute the
entirety of the shock-like state to extensive blood loss within
the injured limb.
Regardless, debate persisted regarding the existence of a spe-
cic toxic factor propagating the same common pathway of
demise in all forms of human shock. The advent of antibiotic
use in the 1940s resulted in a shift from gram-positive to gram-
negative organisms as the predominant bacterial pathogen iso-
lates, which persisted for the ensuing 4050 years (27, 28). Al-
though the concepts of bacterial toxins and endotoxemia had
existed since the late 1800s, it was predominantly in the 1950s
1960s that increasing frequencies of infections with gram-
negative rods produced a clinical picture deemed consistent with
endotoxemic shock (29). The similar clinical presentation of
patients with refractory traumatic shock and with endotoxemic
shock reinvigorated inquiry toward whether a nal common
pathway mediated death in these two populations of critically
ill patients. Interestingly, speculation again focused on the gastro-
intestinal systemas a source of demise, with use of animal models
to explore splanchnic hypoperfusion as an instrumental process
interminal shock fromany cause (30). However, in the late 1960s,
it became increasingly appreciated that patients with coliform
bacterial infections suffered from a clinical process distinct from
that of refractory traumatic shock. Francis Moores writings
in 1969 (29) foreshadow the development of the 1992 consensus
conference denitions of the Systemic Inammatory Response
Syndrome (SIRS: the systemic activation of the innate immune
system, regardless of cause) and sepsis (SIRS infection)
(Table 1):
Unfortunately for our campaign to eliminate the word shock from
the surgical lexicon and thus help to untangle the confusion between
sepsis and trauma there is no other monosyllable that quite does the
job. Still, we would be better off without the word, and our teaching
would be clearer if we never used it, since such a departure would
cause each surgeon or physician to specify causes and mechanisms
rather thancontenting himself with thediagnosis of shock, implying
that all animals and patients in such a state are essentially the same.
Until the late 1980s, sepsis was considered by many to be
near-synonymous with gram-negative endotoxemia (Figure 2)
(27, 31). In the early 1990s, a number of studies led to the concept
that sepsis can arise from microbial infections in the absence of
endotoxin:
1. There was a reemergence of the prevalence of gram-
positive isolates from patients with clinical features of
sepsis (4, 27).
2. Animals infected with Escherichia coli (bearing endotoxin)
or Staphylococcus aureus (no endotoxin) develop equiva-
lent clinical syndromes (32).
3. Clinical trials of monoclonal antibodies neutralizing endo-
toxin failed to show consistent benet in human sepsis (5).
These studies formed the groundwork for the breadthof molec-
ular studies over the last 10 years that argue against a single critical
toxic factor in sepsis. Rather, this work points to a number of
bacterial virulence factors, or microbial-associated molecular
patterns, that can trigger the host response through specic
Centennial Review 133
pattern recognition receptors. These topics have been reviewed
in detail recently (4, 33) and are summarized in Figure 2.
What Role Does the Host Response Play in Sepsis?
Until relatively recently, the preponderance of pathobiological
mechanisms proposed to explain sepsis has focused upon the
course that the pathogen has taken in a ravaged bystander-host.
Ancient peoples believed that epidemics were inicted upon
powerless humans as punishment for wrongdoing (34). In 1892,
Osler wrote that the outcome from sepsis was dependent upon
the dose of the poison from the bacteria and the likelihood
of whether a focus of infection could be evacuated (12). Even
so, Osler struggled with howto intervene upon the host response:
Fever alone is not, I think, hurtful, but it is difcult to differentiate
the effects of fever and of the poisons circulating in the blood. It is not
impossible, as some suppose, that the fever be directly benecial; still,
high and prolonged pyrexia is undoubtedly dangerous and should
be combated.
This debate over the benecial versus harmful effect of the
host response to infection has persisted until today. The notion
of sepsis as an uncontrolled proinammatory response gained
support with the identication of proinammatory cytokines,
most notably tumor necrosis factor (TNF)-, in the late 1980s
(Figure 2). Studies in mice demonstrated protective effects of
antibodies to TNF- during lethal endotoxin challenge. Thus,
TNF- was proposed as a central mediator in sepsis (31). With
numerous clinical trials failing to show benet from interfering
with TNF- and other proinammatory mediators in human sepsis
in the 1990s (5), it has been proposed more recently that there
exists a critical balance between pro- and anti-inammatory me-
diators, and that this balance must be maintained (6). Thus, as
Osler considered in 1892, inhibition of the proinammatory axis
may tip the balance toward immune-suppressive effects of the
anti-inammatory axis, whichmight alsohave detrimental effects
on the host. In reecting upon the numerous failed clinical trials
of the 1990s and the increasingly complex molecular pathways
being elucidated, Roger Bone wrote in 1996 (6): We should
spend more time learning how to achieve an accurate diagnosis
and less time searching for a magic bullet.
In the last 10 years, remarkable progress has been made in
characterizing the critical role of the host and its interaction with
the pathogen in the pathobiology of sepsis. There has been
major advancement in our understanding of molecular signaling
pathways in response to microbial pathogens, including identi-
cation of Toll-like receptors, Nod 1 and Nod 2 intracellular
pattern recognition receptors, and the peptidoglycan recognition
proteins. Additional information is emerging regarding the sys-
temic effects of the inammatory cell response on numerous
target genes that inuence cellular and subcellular processes,
including the microcirculation and mitochondrial function.
These and other recent developments have been reviewed in
detail (4, 17, 35) and are outlined in Figure 2.
The Future
The past century has produced a remarkable explosion of knowl-
edge in the pathobiology of sepsis. Compared with over 2,000
years of belief in the spontaneous generation theory, in the
last 100 years we have progressed from the adoption of the
germ theory of disease to delineating the molecular pathways
of the host-pathogen response. Despite these discoveries, our
current denition of sepsis remains remarkably similar to that
from the time of Osler (Table 1), and little progress has been
made in effective, targeted therapy. To make treatment ad-
vances, we will need to reformulate our notion of sepsis from
that of a general concept (i.e., the host response to infection),
to one of specic diseases characterized by individual pathogens
and recognizable host-response proles (3, 6). Toward this goal,
the 2003 consensus conference proposed a staging system for
sepsis (modeled after the TNM system for cancer), called the
PIRO system, as a template for future investigation (Table 1)
(1). This systemwould stratify patients based on their Predisposi-
tion (e.g., immunosuppressed state, genetic polymorphisms pre-
dicting response to sepsis [4]), Insult infection (e.g., specic
pathogens isolated by culture or bacterial DNA, presence of
endotoxin), Response (e.g., presence of shock, levels of inam-
matory markers, levels of protein C or TNF- that might predict
response to specic types of treatment), and Organ dysfunction
(e.g., organ failure composite score, measures of cellular re-
sponse to insult such as apoptosis or mitochondrial dysfunction).
Thus, while we are still asking the same questions regarding
the pathobiology of sepsis as we did 100 years ago, our answers
are changing and are yielding exciting new discoveries. It is our
hope that the next centennial review of sepsis in the year 2105
will recount the successful application of molecular knowledge
toward the development of effective treatment strategies for
sepsis.
Conflict of Interest Statement : None of the authors has a financial relationship
with a commercial entity that has an interest in the subject of this manuscript.
Acknowledgments : The authors are grateful to Drs. Andrew Onderdonk and Dan
Milner (Brigham and Womens Hospital) for providing the bacterial culture plate
and Grams stain images, respectively (Figure 1B). The authors also thank Drs.
Lior Dolgonos, Scott Schissel, and Laura Fredenburgh for helpful comments.
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