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Science, medicine, and the future: Pathogenesis

of sepsis: new concepts and implications for
future treatment
Pierre-Yves Bochud and Thierry Calandra
BMJ 2003;326;262-266
doi:10.1136/bmj.326.7383.262

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Clinical review

Science, medicine, and the future

Pathogenesis of sepsis: new concepts and implications for
future treatment
Pierre-Yves Bochud, Thierry Calandra

Institute for
Systems Biology,
1441 North 34th
Street, Seattle, WA
98103-8904, USA
Pierre-Yves Bochud
research fellow
Division of
Infectious Diseases,
Centre Hospitalier
Universitaire
Vaudois, CH-1011
Lausanne,
Switzerland
Thierry Calandra
associate professor
Correspondence to:
T Calandra
Thierry.Calandra@
chuv.hospvd.ch
BMJ 2003;326:2626

Severe sepsis and septic shock are important causes of

death in intensive care units. Although our understanding of the pathogenesis of inflammation and sepsis has improved, until recently this has not translated
into clinical benefit. Several new treatment approaches
have given encouraging results. Evidence suggests that
the way forward is to develop pathogen specific
regimens rather than assume that one treatment fits all.

Sources and methods

We selected articles for this review by searching
Medline using the keywords sepsis, therapy, and
Toll-like receptors. We concentrated on publications
on the pathogenesis of sepsis and treatment of septic
shock. As the number of references that could be cited
was limited, we have often referenced review articles
rather than original publications.

Epidemiology and importance of severe

sepsis and septic shock

Further details
about pattern
recognition
receptors and
genetic
susceptibility are
available on
bmj.com

262

Severe sepsis and septic shock are life threatening

complications of infections and the most common
cause of death in intensive care units. However, a lack
of widely accepted definitions of these complications
has made it difficult to obtain accurate estimates of
their frequency. A study published by the Centers for
Disease Control in the United States indicated that the
incidence of septicaemia had increased from 73.6 per
100 000 patients in 1979 to 175.9 per 100 000 patients
in 1987.1 Recent US and European surveys have
estimated that severe sepsis accounts for 2-11% of all
admissions to hospital or intensive care units.2
Although Gram negative infections were predominant in the 1960s and early 1970s, Gram positive infections have increased in the past two decades and now
account for about half of cases of severe sepsis.3 Fungal
infections are also increasing in many countries. Despite
better supportive care, the hospital mortality from
severe sepsis and septic shock (30% and over 60%,
respectively) has not changed much over recent decades.

Innate immune responses to microbial

products
The innate immune system is the first line of defence
against infection and is activated when a pathogen

Summary points
Bacterial cell walls, endotoxins, and exotoxins are
powerful activators of innate and acquired
immune responses
Molecules expressed by pathogens interact with
Toll-like receptors on immune cells, activating the
immune response
Cytokines are important in the pathogenesis of
sepsis
Susceptibility to sepsis may be due to inherited or
acquired mutations of innate immune genes
Severe sepsis and septic shock are clinical
manifestations of a dysregulated immune
response to invasive pathogens
Adjunctive therapy with low dose steroids,
activated protein C or early supportive care can
reduce mortality from severe sepsis and septic
shock
Pathogen recognition receptors (such as Toll-like
receptors) and mediators of sepsis (such as
macrophage migration inhibitory factor) might
be novel targets for treatment

crosses the hosts natural defence barriers.4 It consists

of soluble elements (the alternative and mannanbinding lectin pathways of the complement system,
acute phase proteins, and cytokines) and cellular
elements (monocytes, macrophages, neutrophils, dendritic cells, and natural killer cells). Innate immune
responses must be tightly regulated as unbalanced
inflammatory and immune reactions can result in
either uncontrolled microbial growth or devastating
inflammatory responses with tissue injury, vascular collapse, and multiorgan failure.
Detection of invading microorganisms is mediated
by pattern recognition receptors expressed on the surface of innate immune cells (figure). Pattern recognition receptors recognise structures common to many
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microbial pathogens. These structures are called pathogen associated molecular patterns and include endotoxins (lipopolysaccharide), peptidoglycan, lipoteichoic
acid, lipopeptides, flagellin, mannan, and viral RNA. The
structures are essential for survival of the microorganisms and therefore do not undergo major mutations.
When a pathogen associated molecular pattern
binds to a pattern recognition receptor, it activates
several intracellular signalling pathways resulting in the
activation of transcription factors (NF-B, AP-1, Fos,
Jun). The transcription factors control the expression of
immune response genes and the release of numerous
effector molecules, such as cytokines. Cytokines have an
essential role in orchestrating the innate and acquired
immune responses to an invading pathogen.5

Gram negative bacteria

Gram positive bacteria

Lipopolysaccharide

CpG DNA

Flagellin

Peptidoglycan

Lipoteichoic acid

TLR4

TLR9

TLR5

TLR6-TLR2

TLRX-TLR2

MD-2
CD14

CD14

Bacterial sepsis
Gram negative bacilli (mainly Escherichia coli, Klebsiella
species, and Pseudomonas aeruginosa) and Gram positive
cocci (mainly staphylococci and streptococci) are the
commonest microbes isolated from patients with severe
sepsis and septic shock.3 Fungi, mostly Candida, account
for only about 5% of all cases of severe sepsis.
Gram negative sepsis
Most cases of Gram negative sepsis are caused by
Enterobacteriaceae such as E coli and Klebsiella species.
Pseudomonas aeruginosa is the third commonest cause.
Gram negative infections usually occur in the lung,
abdomen, bloodstream, or urinary tract.
Lipopolysaccharide is an important component of
the outer membrane of Gram negative bacteria and
has a pivotal role in inducing Gram negative sepsis.6
Lipopolysaccharide binding protein in host cells binds
to lipopolysaccharide in the bacteria and transfers it to
CD14.7 CD14 is a protein anchored in the outer leaflet
of the plasma membrane, although it also exists as a
soluble plasma protein that attaches lipopolysaccharide to CD14-negative cells, such as endothelial cells.
CD14 is located in the extracellular space and
therefore cannot induce cellular activation without a
transmembrane signal transducing coreceptor.
A series of remarkable investigations have recently
led to the identification of Toll-like receptor 4 (TLR4)
as the coreceptor for lipopolysaccharide. Toll receptors
were first discovered in Drosophila, where they were
found to have a role in the defence of flies against fungi
and Gram positive bacteria.8 Toll-like receptors were
then identified in other species. Human Toll-like
receptors, like their homologues in insects and other
mammalian species, are type I transmembrane
proteins with an extracellular leucine rich repeat
domain and an intracellular domain homologous to
the interleukin 1 receptor. Genetic studies in mice
showed that mutations in the Tlr4 gene were linked to
resistance to lipopolysaccharide, providing evidence
that TLR4 was an essential component of the lipopolysaccharide receptor complex.9 MD-2, a secreted
protein associated with the extracellular domain of
TLR4, has also recently been shown to have an important role in responsiveness to lipopolysaccharide.10
Gram positive sepsis
Staphylococci (mainly Staph aureus and coagulasenegative staphylococci) and streptococci (Strep pyogenes,
viridans streptococci, Strep pneumoniae) are the
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Specific
signal

Common
signal

Response 1

Specific
signal

Response 2

Interaction between bacterial products and pattern recognition receptors expressed on

immune cells. Components of bacterial cell walls (such as lipopolysaccharide, peptidoglycan,
lipoteichoic acid, flagellin, and unmethylated CpG DNA sequences) interact with specific
Toll-like receptors (TLR) expressed on immune cells. The receptors then activate intracellular
signalling pathways and transcription factors resulting in expression of the gene for immune
response

commonest causes of Gram positive sepsis. They are

usually responsible for infections of skin and soft
tissue, infections associated with intravascular devices,
primary bloodstream infections, or respiratory infections. Gram positive organisms can cause sepsis by at
least two mechanisms: by producing exotoxins that act
as superantigens (see definition below) and by components of their cell walls stimulating immune cells.11
Superantigens are molecules that bind to MHC class
II molecules of antigen presenting cells and to V chains
of T cell receptors. In doing so, they activate large numbers of T cells to produce massive amounts of proinflammatory cytokines. Staphylococcal enterotoxins,
toxic shock syndrome toxin-1, and streptococcal pyrogenic exotoxins are examples of bacterial superantigens.
Gram positive bacteria without exotoxins can also
induce shock, probably by stimulating innate immune
responses through similar mechanisms to those in
Gram negative sepsis. Indeed, Toll-like receptor 2
(TLR2) has been shown to mediate cellular responses
to heat killed Gram positive bacteria and their cell wall
structures (peptidoglycan, lipoproteins, lipoteichoic
acid, and phenol soluble modulin).12

Pathways to sepsis
The clinical manifestations of sepsis produced by different Gram positive and Gram negative bacteria vary. For
example, the clinical pictures of streptococcal toxic
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shock syndrome and meningococcaemia are very different. In addition, E coli urosepsis follows a more benign
course than nosocomial pneumonia due to P aeruginosa.
Moreover, Gram positive and Gram negative sepsis
result in different expression and release of proinflammatory mediators, such as the cytokine tumour
necrosis factor-.13 These observations suggest that there
are specific host immune responses to each pathogen
mediated by various sets of pathogen associated
molecular patterns and pattern recognition receptors.
Toll-like receptors
Of the 10 human Toll-like receptors identified so far,
seven interact with microbial motifs (table 1).4 For
example, TLR2 binds components of the cell wall of
Gram positive bacteria as well as ligands derived from
other pathogens, TLR5 is the receptor for bacterial
flagellin,14 and TLR9 is required for cellular activation
by unmethylated CpG motifs of bacterial DNA.15
Cooperation between Toll-like receptors is necessary
to respond to certain pathogens, such as Gram positive
bacteria and yeast (zymosan).16 Several signal transducing pathways are activated after microbial ligands bind
to Toll-like receptors (figure).17
The fact that different microbial products bind to
different Toll-like receptors, the existence of receptor
specific signalling pathways, and the idea of differential
expression of Toll-like receptors by tissues and organs
strongly suggest that the innate immune system is tailored in a pathogen and tissue specific manner.
Expression of immune genes and host responses to
infections will vary depending on the structural and
biochemical composition of the invading pathogen. If
confirmed, these hypotheses point to the need to
develop pathogen specific approaches to treatment.
Other soluble and membrane associated proteins
have recently been shown to be involved in
recognising bacteria or microbial products. These
include peptidoglycan recognition proteins and
triggering receptor expressed on myeloid cells
(TREM-1). Additional information on these proteins
is available on bmj.com

Table 1 Ligands for human Toll-like receptors and their sources

Receptors

Ligands

Source of ligand

TLR1-TLR2

Soluble factors released by live bacteria

Neisseria meningitidis

TLR2-TLRX

Lipoproteins

Several bacterial species

Lipoteichoic acid

Staphylococcus aureus

TLR2-TLR6

Lipoarabinomannan

Mycobacteria

Phosphatidylinositol dimannoside

Staph aureus

Glycosylphosphatidylinositol anchors

Trypanosoma cruzi

Endotoxin (LPS)

Leptospira interrogans, Porphyromonas

gingivalis

Peptidoglycan

Gram positive bacteria

Soluble phenol modulin

Staph aureus

Zymosan

Yeasts

Macrophage activating lipopeptide-2

(MALP-2)

Mycoplasma fermentans

TLR3

Double-stranded RNA

Virus

TLR4

Endotoxin (lipopolysaccharide)

Gram negative bacteria

Taxol

Plants

TLR5

Flagellin

Flagellated bacteria

TLR7

Imidazoquinoline antiviral compounds

(imiquimod and R-848)

Chemical compounds

TLR9

Unmethylated GpG DNA

Bacteria

264

Adjunctive therapies for sepsis

Numerous adjunctive treatments (that is, other than
antibiotics and supportive care) for severe sepsis and
septic shock have been tested in clinical trials (table 2).
These include neutralisation of microbial toxins such
as lipopolysaccharide, non-specific anti-inflammatory
and immunosuppressive drugs, neutralisation of
pro-inflammatory cytokines, and correction of abnormalities in coagulation. The results have been mixed,18
although several recent clinical trials have given
encouraging results.
Coagulation abnormalities, especially disseminated
intravascular coagulation, are common in patients with
sepsis and microvascular thrombosis. The ensuing
tissue damage may have an important role in the
pathophysiology of organ dysfunction. Treatment with
activated protein C, a protein that has anti-thrombotic,
pro-fibrinolytic, and anti-inflammatory effects, reduces
mortality from severe sepsis at the price of a slight
increase in bleeding events.19
Glucocorticoids exert broad metabolic and immunomodulating effects and have been used to treat several
inflammatory diseases. Although high doses of steroids
have no clinical benefit,18 a recent multicentre trial found
that a seven day course of low doses of hydrocortisone
and fludrocortisone reduced mortality in patients with
septic shock and relative adrenal insufficiency.20 Finally,
two studies of supportive care, one focusing on early
therapy with fluids, vasopressors, and transfusions and
the other on meticulous control of glycaemia with insulin, have shown reduced mortality in patients with severe
sepsis and septic shock.21 22

Future treatment strategies

Microbial drugs and pattern recognition molecules
Designing new drugs to neutralise microbial products
or block their interaction with specific receptor on
immune cells is an attractive concept. Potential targets
include lipolysaccharide binding protein, CD14, TLR4,
and MD-2 for Gram negative sepsis, and CD14, TLR2,
and TLR6 for Gram positive sepsis. Monoclonal
antibodies against CD14 are being evaluated in phase
II studies. Several intracellular signalling molecules,
such as MyD88 and the mitogen-activated protein
kinase are other possible therapeutic targets. However,
inactivating molecules that are pivotal to innate immunity can be harmful, as shown by the increased
sensitivity to bacterial sepsis in mice with mutations of
the Tlr4 gene.23 Careful selection of patients with
severe infections associated with a high probability of
death will therefore be essential.
Macrophage migration inhibitory factor
Macrophage migration inhibitory factor is a cytokine
that has recently been shown to be important in innate
immunity and sepsis.24 It is constitutively expressed in
large amounts by immune, endocrine, and epithelial
cells and is rapidly released after exposure to microbial
products and pro-inflammatory cytokines. Macrophage migration inhibitory factor regulates innate
immune responses to endotoxin and Gram negative
bacteria by modulating the expression of TLR4,
enabling macrophages and other cells at the front line
of defences to respond quickly.25 High levels of macrophage migration inhibitory factor have been detected
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Clinical review

Table 2 Selected antibacterial, anti-inflammatory, and immunomodulating adjunctive therapies investigated in patients with severe
sepsis and septic shock
Type of therapy

Target (s)

Agents

Neutralisation of microbial toxins

Endotoxin

Anti-endotoxin antibodies, anti-lipid A antibodies,

lipopolysaccharide analogues, lipopolysaccharide removal

Non-specific anti-inflammatory and

immunomodulating drugs

Multiple inflammatory and immune mediators

High dose corticosteroids, low dose corticosteroids,

pentoxifylline, immunoglobulins, interferon gamma

Inhibition of specific mediators

Pro-inflammatory cytokines:
Tumour necrosis factor

Anti-tumour necrosis factor antibodies, soluble tumour

necrosis factor receptors

Interleukin-1

Interleukin-1 receptor antagonist

Phospholipid components:
Phospholipase A2

Phospholipase A2 inhibitor

Cyclo-oxygenase

Ibuprofen

Thromboxane

Dazoxiben, ketoconazole

Platelet activating factor

Platelet activating factor antagonists, platelet activating factor

acetylhydrolase

Oxygen free radicals

Correction of coagulopathy

N-acetylcysteine, selenium

Nitric oxide

N-methyl-L-arginine

Bradykinin

Bradykinin antagonist

Coagulation cascade

Antithrombin III, tissue factor pathway inhibitor, activated

protein C

Other

Prostaglandin E1, granulocyte colony stimulation factor

in patients with inflammatory and infectious diseases,

including severe sepsis and septic shock.26
Immunoneutralisation of macrophage migration
inhibitory factor or deletion of the Mif gene protects
mice against lethal endotoxaemia, Gram positive toxic
shock syndromes, and experimental bacterial peritonitis.
Conversely, mice injected with macrophage migration
inhibitory factor together with live bacteria or microbial
toxins have increased death rates.2628 This factor thus
has the potential to endanger life when expressed in
excess during sepsis. Development of drugs to block the
production of macrophage migration inhibitory factor
or inhibit its function may help treat severe sepsis and
other inflammatory diseases.

3
4
5

6
7
8
9

High mobility group protein 1

High mobility group protein 1, a protein previously
known as DNA binding protein regulating gene
transcription and stabilising nucleosome formation, has
recently been described as a late mediator of
inflammation and sepsis.29 Patients with septic or haemorrhagic shock have raised serum concentrations of
high mobility group protein 1, and concentrations are
associated with patients outcome. Use of polyclonal
antibodies to block high mobility group protein 1 in
mice protects them against lipopolysaccharide induced
acute lung injury and lethal endotoxaemia.30

10

11
12

13

14

15
16

Genetic studies of susceptibility to sepsis

Several gene polymorphisms have been associated
with increased susceptibility to sepsis (see bmj.com for
more information). Testing for polymorphisms of
important genes may help to identify people who are
at increased risk of sepsis when exposed to virulent
bacteria and who may benefit from targeted immunomodulatory therapies.
Funding: TC and P-YB are supported by grants from the Swiss
National Science Foundation (31-066972.01 and 81LA-65462).
TC is the recipient of a career award from the Leenaards
Foundation.
Competing interests: TC has been reimbursed for travel
expenses and received fees for speaking at conferences
organised by Eli Lilly, the manufacturer of Xigris, recombinant
activated protein C.

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17
18

19

20

21

22

23

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Lesson of the week

Low dose methotrexate and bone marrow suppression
Michael Sosin, Sunil Handa
Department of
Haematology,
Sandwell General
Hospital, West
Bromwich, West
Midlands, B71 4HJ
Michael Sosin
senior house officer
Sunil Handa
consultant
haematologist
Correspondence to:
Sunil Handa
sunil.handa@swellhot.
wmids.nhs.uk
BMJ 2003;326:2667

Methotrexate is an antimetabolite that, apart from its

use in malignant disorders, is taken orally in low doses
for the control of conditions such as rheumatoid
arthritis and psoriasis. When used in chemotherapy it
causes profound suppression of bone marrow.
However, even at a low dose it may be associated with
bone marrow suppressionparticularly in the presence of renal insufficiency or when other drugs are
taken concomitantly (box 1). Its unusual weekly dosing
regimen can result in dose error by patients or
clinicians. We present three cases of bone marrow suppression in patients taking low dose methotrexate who
presented at a district general hospital during a period
of four years (table).

Case reports
Case 1
A 78 year old woman with rheumatoid arthritis had
been taking a weekly dose of 17.5 mg of methotrexate
for two months. Before this the dose had been gradually built up over several years. She was admitted with
breathlessness and found to be pancytopenic (haemoglobin concentration 100 g/l, white cell count 3.0
109/l, neutrophils 2.5 109/l, platelets 13 109/l). A
month earlier her full blood count had been normal.
Methotrexate treatment was discontinued. She was
treated with intravenous folinic acid and antibiotics and
was given transfusions of blood products. Her blood
count showed recovery (haemoglobin concentration
137 g/l, white cell count 11.0 109/l, neutrophils 8.1
109/l, platelets 178 109/l). After a prolonged admission
of about four weeks she was discharged home well.
Case 2
A 67 year old man with rheumatoid arthritis had been
taking methotrexate for six months. He was admitted

with diarrhoea and vomiting. Both he and his family

were unclear about the dose of methotrexate he had
taken recently, but it seemed likely that he had been
taking methotrexate daily instead of weekly. He was
pancytopenic (haemoglobin concentration 102 g/l,
white cell count 1.2 109/l, neutrophils 0.3 109/l,
platelets 66 109/l). A month previously his blood
count showed a neutrophilia (haemoglobin concentration 111 g/l, white cell count 15.5 109/l, neutrophils
13.7 109/l, platelets 393 109/l). His weekly dose of
methotrexate had been increased from 5 mg to 7.5 mg
at that time, and this may have resulted in the
presumed dose error.
Methotrexate was discontinued, and he was treated
with blood transfusion and with intravenous antibiotics
and folinic acid. His blood count recovered (haemoglobin concentration 117 g/l, white cell count 15.6
109/l, neutrophils 8.5 109/l, platelets 153 109/l),
and he was discharged home well.
Case 3
A 74 year old woman, who had been taking
methotrexate (5 mg weekly) for 10 years, was admitted
with abdominal pain and pancytopenia (haemoglobin
concentration 78 g/l, white cell count 0.5 109/l, neutrophils 0.4 109/l, platelets 14 109/l). She had
received a course of trimethoprim for a presumed urinary tract infection one week before admission. Three
weeks earlier her blood count had been normal.
Methotrexate was discontinued. She was treated
with intravenous antibiotics and folinic acid and transfusion of blood products. She did not improve and was
started on treatment with granulocyte colony stimulating factor. Her white cell count rose rapidly, and her
last blood count showed a neutrophilia (haemoglobin
concentration 132 g/l, white cell count 52.0 109/l,
neutrophils 48.4 109/l, platelets 190 109/l). After

Details of patients with bone marrow suppression after taking methotrexate

Patient

Age, sex

Weekly dose of
methotrexate (duration of
treatment)

78, female

17.5 mg (2 months)

Rheumatoid arthritis

Shortness of breath

67, male

5 mg (6 months)

Rheumatoid arthritis

Diarrhoea and vomiting

Dose error

74, female

5 mg (10 years)

Rheumatoid arthritis

Abdominal pain

Concomitant trimethoprim

Died

4*

40, male

10 mg (7 months)

Psoriasis

Fever and rigors

Unprescribed self
treatment

Recovered

Indication

Symptoms at
presentation to hospital

Precipitating factor

Outcome

Unknown

Recovered
Recovered

*Not described in the text.

266

BMJ VOLUME 326

1 FEBRUARY 2003

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