Download The Problems and Challenges of Immunotherapy

CHEST
VOLUME 123 / NUMBER 5 / MAY, 2003 Supplement
The Problems and Challenges
of Immunotherapy in Sepsis*
Stanley A. Nasraway, MD, FCCP
Despite decades of research, the morbidity and
mortality of sepsis and septic shock remain very
high. To further compound the problem, results
from all investigative trials (with one exception) have
shown that tested immunotherapies aimed at modulating the excessive expression of key cytokines, such
as the interleukins and tumor necrosis factor, have
been either equivalent or inferior to placebo. While
controversy prevails in terms of continuing such
investigative trials, study designs can be held accountable for inherent flaws. Testing for the wrong
hypothesis, errant study design, using the wrong
agent, focusing on an inappropriate target group,
excessive expectations, and uncontrolled variables
have potentially obscured the real efficacy such
agents might have to offer. By standardizing protocols and reducing uncontrolled variables, research
can be more precisely targeted so as to unmask the
real benefits to the patient.
(CHEST 2003; 123:451S– 459S)
Key words: cytokines; immunomodulators; sepsis; sepsis trials;
septic shock
Abbreviations: CI ⫽ confidence interval; FDA ⫽ US Food and
Drug Administration; IL ⫽ interleukin; MAb ⫽ monoclonal antibody; NO ⫽ nitric oxide; PAF ⫽ platelet activating factor;
PROWESS ⫽ Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis; rhIL-1a ⫽ recombinant human
IL-1 receptor antagonist; TNF ⫽ tumor necrosis factor
epsis and septic shock are significant causes of patient
S morbidity
and mortality. Approximately 750,000 cases
1
of severe sepsis occur in the United States each year,
secondary to bacterial and fungal infections.2 In half of
*From the Department of Surgery and Section of Critical Care
Research, Tufts-New England Medical Center, Tufts University
School of Medicine, Boston, MA.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Stanley A. Nasraway, MD, FCCP, Department of Surgery, Tufts-New England Medical Center, 750 Washington St, Box 4630, Boston, MA 02111; e-mail: Snasraway@
lifespan.org
www.chestjournal.org
these patients, shock develops that is refractory to fluid
resuscitation.1 Thirty years ago, mortality from septic or
cardiogenic shock exceeded 70%3; today, the rate for
septic shock is still high, at 50%, despite the availability of
potent antibiotics and intensive supportive care.4,5
Overall, the incidence of sepsis and septic shock is
escalating. From 1979 to 1987, the percentage of infectious disease diagnoses that included sepsis rose from 9 to
25%.6 This upsurge has been attributed to a host of
factors, including the increased use of cytotoxic and
immunosuppressive therapies, the aging of the population,
a heightened frequency of infection from antimicrobialresistant pathogens, and the increased use of invasive
devices, such as intravascular catheters.7
Is Research Striking Out?
Sepsis treatment consists of appropriate antibiotic therapy and effective surgical eradication of the septic sources
whenever possible. Yet, mortality rates remain high—
why? The past decade has been a time of greater understanding of the inflammatory response and of organ
dysfunction during overwhelming infection; however, this
enhanced knowledge at the research level has not generally translated into clinical success. Trial results of immunotherapies for severe sepsis or septic shock, up to the
spring of 2000, have been dismal. Three major trials of
septic shock—the Immunex (Immunex Corporation; Seattle, WA) phase II study of the p80 soluble receptor to
tumor necrosis factor (TNF),8 the Glaxo-sponsored (Glaxo
SmithKline; Research Triangle Park, NC) study of nitric
oxide (NO) synthase inhibition,9 and the Centocor (Centocor; Malvern, PA) phase IIIb anti-endotoxin trial of
human monoclonal antibody (MAb) HA-1A10— have culminated in excess mortality in patients receiving the
experimental agent. A meta-analysis11 of 15 clinical trials12–25 that used nonglucocorticoid anti-inflammatory
agents demonstrated no statistical benefit of immunomodulation, although a modest positive outcome may exist
(odds ratio, 1.11; 95% confidence interval [CI], 0.99 to
1.23; p ⫽ 0.07). Since the publication of this metaanalysis, the results of other phase III trials have been
reported, including anti-TNF studies.5,26 These also failed
to demonstrate any clinical benefit.
In 1998, Glaxo Wellcome terminated its international
trial of L-NG-methylarginine hydrochloride, a nonselective NO synthase inhibitor, for the treatment of patients
with septic shock. The agent simulates a vasopressor by
restoring vasomotor tone. An interim analysis in this trial
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of the first 522 patients who received this experimental
agent demonstrated a significant increase in mortality.27
In addition to the Centocor phase IIIb trial of HA-1A,10
four other anti-endotoxin studies28 –31 have produced disappointing results. For example, in the study by Bone and
colleagues28 that evaluated the safety and efficacy of E5, a
murine MAb directed against endotoxin, no significant
improvement in survival after 30 days was observed in
patients who received the agent as compared with those
who received placebo (p ⫽ 0.21). The same lack of significant response was noted in a study by Ziegler and
colleagues30 of HA-1A in Gram-negative sepsis in which
the mortality rate was 43% and 39%, respectively, in the
placebo and the human monoclonal IgM antibody groups
(p ⫽ 0.24). More recently, a phase IIIc trial31 examining
the use of E5 in 915 patients with confirmed severe
Gram-negative sepsis once again demonstrated no appreciable survival benefit. These disheartening investigational
outcomes that showed no benefit and, in some cases, an
increase in mortality in patients with sepsis raise serious
questions about the path of future clinical investigations.
The Immunomechanisms of Sepsis
Sepsis involves a complex interaction of proinflammatory
and anti-inflammatory mediators (Table 1). The net effect of
a given mediator can vary depending on the state of activation of the target cell, the presence of other mediators, and
the ability of the target cell to release mediators that can
augment or inhibit the primary mediator.32 Although the
actions of many cytokines and cells are involved, TNF-␣ is
considered the primary mediator of sepsis.32 Evidence supporting an important role for TNF-␣ includes the observations that endotoxin injected in healthy humans results in the
detection of free TNF-␣ in plasma and the development of
many signs and symptoms associated with Gram-negative
infection. TNF-␣ release leads to activation of other cytokines, such as interleukin (IL)-1␤ and IL-6, that are associated with cellular damage.32,33 TNF-␣ has received much
attention because it is elevated in most patients with sepsis;
however, TNF-␣ levels are also amplified in many healthy
people as well as patients with sepsis, and those with a variety
of diseases.32 IL-6 may be a more consistent predictor of
sepsis because it remains elevated for a longer period of time
than TNF-␣, and it appears to better correlate with sepsis
severity and mortality.34,35 Circulating concentrations of IL-8
also correlate with severity of sepsis and mortality.36
Table 1—Pro-inflammatory and Anti-inflammatory
Mediators in Sepsis
Pro-inflammatory Mediators
TNF-␣
IL-1␤
IL-6 (released from activated
macrophages)
IL-8
PAF
Leukotrienes
Thromboxane A2
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Anti-inflammatory
Mediators
IL-receptor antagonist
IL-4
IL-10
Through the actions of these aforementioned mediators, a variety of cells become activated, initiating cascades
believed to be detrimental to the host (Fig 1). A long list
of strategies has been developed to reverse or control the
inflammatory processes initiated with sepsis, including
antibody against lipopolysaccharide (endotoxin), IL-1 receptor antagonist, platelet activating factor (PAF) antagonist, anti-TNF-␣ antibody, and polyclonal Ig.28,37,38 One of
the first interventions to gain attention was direct inhibition of the effects of endotoxin using specific MAbs;
however, as mentioned, studies28,30 conducted with MAbs
such as HA-1A and E5, which bind to the lipid A portion
of the endotoxin molecule, have failed to demonstrate
positive clinical outcomes in patients with sepsis, perhaps
suggesting that the time window to reduce the endotoxininitiated sepsis cascades had passed by the time treatment
was started. Research in sepsis immunotherapy continues
(Table 2).32,33,39,40 The question remains—at what cost?
The Flaws in Sepsis Investigations
While inadequate outcomes with respect to human
sepsis research have been demonstrated in the past, such
research should continue; however, substantial changes
must be made in the way we study new inflammatory
modulators to sidestep the flaws in the study designs of the
past decade (Table 1). Reasons abound to explain the
failures of previous clinical sepsis studies.9,28,41
The Wrong Hypothesis
Perhaps the hypothesis that excessive and poorly regulated intravascular inflammation is causal for shock, multiple organ failure, and death in the septic host is wrong.
Anti-TNF strategies have been successful in animal models of severe infection induced by endotoxin.42,43 In the
study by Opal and colleagues,43 mice were given cyclophosphamide, rendered neutropenic, injected with a lethal dose of Pseudomonas aeruginosa, and denied antibiotics. The mice were then placed in four groups: those
receiving an irrelevant MAb (placebo), those receiving
anti-TNF MAb, those receiving MAb directed against
P aeruginosa lipopolysaccharide, and those given a combination of anti-TNF and anti-lipopolysaccharide MAb
(group 4). The mice given the placebo quickly died, while
those given either the anti-TNF or anti-lipopolysaccharide
had approximately a 40% survival rate. Those mice given
the combination had an approximate 75% survival rate.
The results were encouraging enough to attempt to treat
humans in the same manner.
However, the primary hypothesis might be wrong.
Runaway inflammation may not be responsible for the
morbidity and mortality related to sepsis; in this case,
immunotherapy alone would not be expected to reverse
shock. Rather, the combination of antimicrobial therapy,
fluid therapy, inotrope and vasoactive drug support, and
ventilatory support in conjunction with immunotherapy
would be considered equally vital as a therapeutic strategy.
In addition, preclinical investigations supporting the underlying hypothesis or study agents may have been insufficient. Animal models of sepsis have limited applicability
and may not properly replicate human sepsis.
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Figure 1. The cytokine cascade. G-CSF ⫽ granulocyte colony-stimulating factor.
Right Question, Wrong Study Design
Flaws in experimental design are undoubtedly partly
responsible for many of the failures of past sepsis trials.
Studies examining the role of recombinant human IL-1
receptor antagonist (rhIL-1ra) may be an example of this.
A phase IIIa study by Fisher and colleagues13 attempted
to define the efficacy of rhIL-1ra in the treatment of sepsis
syndrome. The study was designed to give the 893 patients
with sepsis syndrome an IV loading dose of rhIL-1ra,
Table 2—Therapeutic Sepsis Interventions in
Clinical Trials
Antioxidants (procysteine)
Anti-TNF antibodies
Bactericidal permeability increasing protein
Corticosteroids
Granulocyte colony-stimulating factor
Hemoglobin solutions (eg, NO scavengers)
Hemoperfusion with polymixin B
High-density lipoproteins
Immunonutrition (fish oil)
Inhibitors of NO synthase
Lipopolysaccharide analogues
Recombinant PAF inhibitor
TNF receptor p55
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100 mg, or placebo followed by a continuous 72-h IV
infusion of rhIL-1ra (1.0 mg/kg/h or 2.0 mg/kg/h) or
placebo. The results of the trial showed no statistical
benefit of giving the agent over the placebo (Fig 2);
however, a subgroup analysis suggested that sicker patients did, in fact, respond to the continuous rhIL-1ra
infusion. The study was subsequently redesigned for a IIIb
phase. Investigators wanted to enroll patients who were
more ill in an attempt to take advantage of the previous
findings; however, the phase IIIb enrollment criteria in
the subsequent study for sepsis and severity were almost
identical to the criteria used in the phase IIIa study.
Investigators also wanted to enroll patients who were more
likely to sustain hypotension. Unfortunately, the definition
of hypotension as a mean arterial pressure of ⬍ 70 mm Hg
was lowered only to 65 mm Hg. These sorts of subtle
changes in the study undermined the likelihood of finding
a meaningful difference. The results of the phase IIIb trial
were identical to those of the failed phase IIIa trial.12
Right Question, Wrong Agent
Clinical investigation is arguably premature, given the
extreme complexity of the inflammation cascade and the
current limitations in our understanding of the underlying
fundamental biology. As investigators, we have to be
careful about interpreting the information presented to us
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Figure 2. The results of a study by Fisher and colleagues13 using recombinant human interleukin-1
receptor antagonist for the treatment of sepsis syndrome. IL-1ra ⫽ IL-1 receptor antagonist.
from animal and early clinical trials. Companies fueled by
venture capital and eager to turn a profit try to put the best
face on their data to sustain themselves. A small phase II
trial funded by Immunex tested a P-80 TNF receptor, a
recombinant, soluble fusion protein that is a dimer of an
extracellular portion of TNF receptor and the Fc portion
of Ig G1, and which binds and neutralizes TNF-␣, preventing death in animal models of bacteremia and endotoxemia.8 The results in humans were devastating. Basically, in dose-related fashion, the higher the dose of the
P-80 receptor, the higher the mortality rate. There was a
30% mortality among the 30 patients receiving the low
dose, a 48% mortality among the 29 patients receiving the
middle dose, and 53% mortality among the 49 patients
receiving the high dose (p ⫽ 0.02). Baseline differences in
the severity of illness did not account for the increased
mortality in the groups receiving the higher doses of the
P-80 receptor. The efforts of Immunex efforts to use the
P-80 TNF receptor to treat sepsis were abandoned after
this trial; however, when the same drug was used in
rheumatoid arthritis, another inflammatory disease but
one with greater chronicity as compared with severe
sepsis, the results were astoundingly positive.
Right Question, Wrong Target Group
The enrollment criteria of the premier sepsis studies in
the past decade have been exclusively dependent on overly
sensitive, nonspecific clinical signs. Rather than the entire
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sepsis population, perhaps the focus should be on a
narrower cohort of severely ill patients with reversible
physiology. A 1991 study29 using E5 anti-endotoxin in
patients with septic shock demonstrated that the agent
also appeared to be beneficial when used in patients with
nonseptic shock. The cohort became too broad to prove
the worth of this agent when compared to placebo.
Inclusion criteria were few in number and incorporated
virtually omnipresent and nonspecific signs/symptoms
such as altered mental status and a respiratory rate ⬎ 20
breaths/min. A study31 designed to again prove the efficacy
of E5 in patients with either septic or nonseptic shock also
failed, due to targeting a very heterogeneous patient
population. Studies such as these have been driven by
premature and spurious findings from post hoc, subgroup
analyses. This case represents ⬎ 20 years of anti-endotoxin
research and has not provided definitive answers about
mortality reduction.
Excessive Expectations
In the 1990s, researchers hoped to dramatically increase survival in patients with septic shock and sepsis by
as much as 50%. Such expectations of “hitting a home run”
were built into the early studies. An animal study by
Hinshaw and colleagues44 determined the efficacy of
treatment with anti-TNF MAb in preventing the deleterious effects of sepsis in a nonhuman primate. Experiments were carried out using baboons IV infused with a
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lethal dose of Escherichia coli. Twelve baboons (6 control
and 6 experimental) received infusions of E coli. The
experimental group was administered a bolus of anti-TNF
antibody 30 min after the E coli infusion. Control baboons
lived an average of 19 h, while the MAb-treated baboons
survived ⬎ 7 days with a significantly improved quality of
life compared to the control group. The results of this
study launched tremendous interest in TNF as a molecule
that could be immunomodulated.
The next step was to try the agent on humans. Abraham
and colleagues20 conducted a multicenter, placebocontrolled trial that tested TNF-␣ in ⬎ 900 patients with
severe sepsis. Patients were administered placebo, lowdose TNF-␣, or high-dose TNF-␣. The outcome measure
was 28-day mortality. At day 28, the reduction in mortality
for all severely septic patients was not significantly different for either dose of TNF-␣ relative to placebo; however,
a substantial trend in increased survival was evident in the
subset of patients with septic shock receiving either dose
of the TNF antibody, and this improvement was sustained
throughout the 28-day period. This triggered a second trial
that precisely reproduced the first study design in the
hope of amplifying the survival rates for strict septic shock
seen in the original study.5 Surprisingly, despite an identical experimental design and a much larger sample size,
the results were not positive: 40.3% of the 948 patients
who received TNF and 42.8% of 930 who received
placebo had died by day 28 (95% CI, 0.02 to 0.07;
p ⫽ 0.27). Thus, no association was seen between therapy
with TNF and increased rapidity in reversal of initial shock
or prevention of subsequent shock.
Studying the use of TNF in sepsis continued, but with
a change in perspective. In septic shock patients, high
amounts of circulating TNF-␣ and IL-6 were found to
correlate with fatal outcome45; however, in trauma patients, and even those patients resuscitated from hemorrhagic shock, much less increased concentrations of IL-6
were detected while normal TNF-␣ circulating concentrations were measured. In these patients, cytokine concentrations did not correlate with outcome. This finding
suggests a much higher degree of activation of the immunoinflammatory cascade in septic shock than in patients
with multiple trauma. Increased IL-6 levels are now
considered an indicator of the development of a nosocomial infection in trauma patients (Fig 3).
Recently, Knoll Pharmaceuticals (Mount Olive, NJ)
completed its North American study of anti-TNF for
patients with severe sepsis; at the time of this writing, the
results have been presented but not published.46 The
Knoll Pharmaceutical approach differs from the earlier
studies in that it looks not just at clinical signs of sepsis, but
also at levels of inflammatory cytokines, specifically IL-6.
Knoll Pharmaceuticals integrated an IL-6 semiquantitative
assay with its MAb study because it found in phase II trials
that patients whose IL-6 levels are ⬍ 1,000 pg/mL are
less likely to benefit from receiving anti-TNF-␣, whereas
those patients with severe sepsis who have IL-6 levels
⬎ 1000 pg/mL do appear to benefit from anti-TNF.18 The
final results of this phase III trial demonstrated a significant reduction in mortality, more so in that subset of
patients with very high IL-6 concentrations at study
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enrollment. Absolute mortality was reduced by 3.6%
(p ⬍ 0.05). In association with this, multiple organ dysfunction was similarly decreased during the first week in patients
receiving anti-TNF. The decrease in mortality may not be
clinically striking enough for US Food and Drug Administration (FDA) approval, which remains tenuous at best for
this agent.
Too Many Uncontrolled Variables
Unlike animal studies, researchers investigating immunotherapy for clinical septic shock have not controlled for all the variables. The best example is the
Glaxo Wellcome study that aimed to nonselectively
inhibit the synthesis of NO. NO is a short-acting, potent
vasodilator derived from the enzymatic oxidation of
arginine. Under pathophysiologic conditions, stimulated
by cytokines, the inducible form of NO becomes diffusely expressed, producing large amounts of NO. This
has been implicated, for example, in the cardiovascular
failure of septic shock.47,48
Pharmacologic inhibition of NO production has been
investigated as an adjunct to standard therapies of septic
shock.48,49 Glaxo Wellcome tested its NO synthase inhibitor, 1-n-methyl arginine, in a multicenter international
study that was expected to be the largest trial ever in septic
shock, with almost 5,000 patients. The end points were
14-day and 28-day mortality, as well as 7-day resolution of
shock because of the vasopressor action associated with
NO synthase inhibition; however, a key flaw in the experimental design was the wide and high range of mean
arterial pressures to which vasopressors and the experimental agent were titrated: 70 to 90 mm Hg. Usual
practice in North America would be to titrate BP to a
minimum mean arterial pressure of 60 to 70 mm Hg;
however, in other parts of the world, mean arterial
pressures are maintained at 80 to 90 mm Hg in the
severely septic patient, a level that can be deleterious
given the need for vasopressors.50 There is no clinical
evidence to support this practice. The Glaxo Wellcome
trial was stopped after interim analysis when an increase in
mortality in the group of patients receiving the experimental agent was observed. This mortality was due to hemodynamic compromise: pulmonary hypertension, rightheart failure, and a low cardiac index (S. Grossman;
personal communication; April 1998). The increasing
doses of the vasopressor caused a subsequent increase in
afterload that aggravated cardiac failure in those patients
already in circulatory shock.51 Also, other variables were
noted. For example, patients were recruited from around
the world: from Chile to Poland, from Canada to Singapore. This sort of widespread enrollment necessarily incorporated into the trial differences in physician practice
and in the types of patients studied; variability related to
physician and patient heterogeneity was uncontrolled and
unaccounted for. Enrolled patients had to have been too
diverse, with differences in comorbidities, severities of
illness, types of infecting pathogens and sources of infection. Conventional management was variable and uncontrolled. Variability in investigator sites, country/cultural
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Figure 3. Serum TNF-␣ and IL-6 in septic shock.45
differences, and dissimilarities in the time to patient
randomization from sepsis onset were also differences that
confounded the results.
The Way Forward
Standardizing conventional practice is one way to sidestep the uncontrolled variables and heterogeneity of patient populations. Enrollment criteria for sepsis studies
have been largely based on uniform definitions for sepsis,
severe sepsis, and septic shock developed by the American
College of Chest Physicians/Society of Critical Care Medicine Consensus Conference.52 Some studies and commentaries53–56 have critiqued these criteria as too sensitive,
failing to target selectively the patient subgroup that is
more likely to benefit from the experimental therapy. Lack
of selectivity, as previously discussed, also aggravates the
problem of patient heterogeneity.
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Future studies will fail if based on the same old
methods. Future studies that propose to modulate inflammation should not use enrollment criteria that rely exclusively on clinical signs of inflammation. Heterogeneity
must be reduced. Sample sizes in much of the earlier
research were too small, mainly as a result of overestimation of mortality risks and overly enthusiastic expectations
in the potential benefits of immunomodulation. Larger
sample sizes are therefore needed to unmask the relatively
small beneficial effects of immunomodulation. Dosing is
important; previously, the interventions tested were often
ineffective in that doses studied were too high, too low, or
too few. Also, the 28-day mortality end point mandated by
the FDA may be too rigid or too crude, and may represent
the wrong end point, in any event. Instead, the reversibility of organ failure or circulatory shock should be the
focus. The severity of disease in many trials has been too
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low or too high. In some studies, patients were not
stratified for illness severity. Finally, inadequate monitoring or quality control of investigation sites, in conjunction
with lucrative per capita reimbursement, encourages enrollment of inappropriate patients.
Patient enrollment should be more selective, using
scoring systems for illness severity, focusing on specific
infection sources,57 and documenting biochemical inflammatory excess. Treatment protocols should be employed
to reduce uncontrolled variables in physician practice that
can alter cytokine expression.9 In addition to reducing the
mortality in patients receiving the experimental agent, the
use of standardized protocols can reduce mortality in
patients randomized to the control group, since setting the
rules for the process of care tends to decrease variability
and errors, while improving quality.58,59
Attention to detail and revision of prior hypotheses led
to two successful trials of immunotherapy. Investigators
for Eli Lilly and Company (Indianapolis, IN) completed a
phase III trial of 1,690 patients with severe sepsis or septic
shock (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS]) showing
that administration of human recombinant activated
protein-C decreased 28-day mortality.60 The hypothesis
for which this agent was studied is novel, and states that
during severe sepsis, clinically undetectable microthromboses develop, occlude capillary flow, and result in organ
ischemia and multiple organ dysfunction. In fact, animal
and human studies have shown that protein-C concentrations are dramatically reduced in patients and, further,
that protein-C concentrations correlate inversely with
death.61 In the PROWESS study, administration of activated protein-C continuously for 96 h yielded an absolute
mortality reduction of 6.1% (p ⫽ 0.005); however, this
study was highly selective, in that many patients who
might be prone to bleeding from a naturally occurring
anticoagulant such as activated protein-C were excluded,
such as those with hepatic or renal failure, a history of
recent bleeding, or recent surgery. A separate monitoring group was responsible for ensuring purity of enrollment and screened and approved patients for study entry. Interestingly, initial review of the data from the
PROWESS study did not clearly show a reduction in
multiple organ dysfunction. Also, it appears, based on the
FDA review, which is documented in the product label,
that the sickest half of patients are the more likely
subcohort to benefit. Activated protein-C may benefit
patients by a multipronged action, in that it is an antiinflammatory agent and also attenuates cellular death, ie,
apoptosis.62
The second, and equally compelling trial, was French
Steroids in Septic Shock Trial, the results of which were
reported at the 30th International Educational and Scientific Symposium of the Society of Critical Care Medicine
in February of 2001 and recently published.63 Prior efforts
at using pharmacologic doses of glucocorticoids for septic
shock had decisively failed to show benefit.64,65 Based on
the numerous observations that as many as half to two
thirds of patients in septic shock may sustain relative
adrenal insufficiency, French investigators at 19 ICUs
tested the hypothesis that giving physiologic doses of
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Table 3—Comparison of Mortality Reductions Among
the Successful Trials for Immunomodulation
Relative Risk of
Absolute %
Death (95% CI)* p Value Reduction in Risk
Variables
Anti-TNF
Activated protein-C
Hydrocortisone
0.90
0.81 (0.69–0.94)
0.84†
0.049
0.005
0.02
3.6
6.1
10
*Relative risk is calculated as the mortality rate in the experimental
group divided by the mortality rate in the placebo control group.
†For patients with adrenal insufficiency; hazard ratio ⫽ 0.67 (95%
CI, 0.47– 0.95).61
glucocorticoids and mineralocorticoids would improve adrenergic responsiveness, resulting in reversal of circulatory
failure and improved survival.63 This prospective randomized trial in 299 patients in septic shock decreased mortality by 16% (absolute reduction 10%) for patients with
adrenal insufficiency (229 of 299 studied patients), as
determined by a short adrenocorticotropic hormone stimulation test (Table 3). There was no benefit evident for
corticosteroid administration to those patients who were
adrenocorticotropic hormone responders.
Conclusions
Sepsis and septic shock continue to cause high rates of
morbidity and mortality. Although our understanding of
the role of inflammation in these conditions is increasing,
10 years of intense clinical research with immunotherapy
has not yet yielded a successful treatment adjunct. More
attention must be paid to study design in terms of
eliminating variability in end points, focusing on the
appropriate target groups, standardizing care, and having
more realistic expectations. Research in this field must and
will continue, necessitated by the high mortality seen in
septic shock. One can expect that with continuous improvements in experimental design, more extensive preclinical research, and investigative tenacity, it is inevitable
that immunotherapeutic adjuncts will be proven useful.
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