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556 PART 5: Infectious Disorders

histocompatibility complex on chromosome 16 and is a prominent Another recent trial coupled biomarker data to use of GM-CSF
antigen-presenting surface molecule. Thus, it would seem central to as an immunostimulatory therapy and demonstrated a significant
induction and maintenance of pathogen-directed immune responses. 116-119 reduction in duration of mechanical ventilation. This then appears
139
mHLA-DR has already been reported as a biomarker for assessing the to be the proper approach for future trials of any of the agents being
impact of immunostimulating interventions. 51,87,120,121 contemplated to ameliorate excessive immunosuppression in septic
■ FUTURE THERAPEUTIC APPROACHES patients, whether it be further study of G- or GM-CSF or other prom-
ising agents that block apoptosis, block negative costimulatory mol-
To date, testing new biologic therapies for sepsis has been frustrat- ecules, decrease the level of anti-inflammatory cytokines, or increase
ing, and over 25 trials of new agents have failed. Almost all of these HLA-DR expression.
122
trials focused on attenuating the initial inflammatory response while
ignoring—and possibly exacerbating—the development of a state of
immunosuppression. 30,35,38 In these trials, as in most cases of sepsis KEY REFERENCES
managed in the ICU, the majority of deaths occurred in these immuno-
suppressed patients. 35,123-125 • Calvano SE, Xiao W, Richards DR, et al. A network-based analysis
Two main strategies of immunostimulation have been studied in of systemic inflammation in humans. Nature. 2005;437:1032-1037.
patients suffering from severe sepsis: IFN-γ and granulocyte- macrophage • Carson WF, Cavassani KA, Dou Y, Kunkel SL. Epigenetic regula-
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settings. Unfortunately these therapies have not been shown to confer • Hobson MJ, Wong HR. Finding new therapies for sepsis: the need
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As we move into the future in this field, new therapies that are Care. 2011;15:1009.
identified from animal model and translational research will no doubt
be guided by use of biomarkers that best characterize immune status • Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death
in patients and help determine populations of patients most likely to and inflammation in sepsis. Nat Rev Immunol. 2006;6:813-822.
respond to immunostimulatory interventions. 126 • Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith
The change of mHLA-DR over time is perhaps our most promising CM, Karl IE. Accelerated lymphocyte death in sepsis occurs by
current biomarker to employ in this regard. Results expressed as a change both the death receptor and mitochondrial pathways. J Immunol.
over two time points provide excellent predictive values, especially 2005;174:5110-5118.
change calculated between days 0 and 3 or between days 0 and 7 (areas • Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced
under the curve of 0.92 and 0.94, respectively, in receiver operating apoptosis causes progressive profound depletion of B and CD4+ T
characteristic analysis). Other studies show that a depressed slope of lymphocytes in humans. J Immunol. 2001;166:6952-6963.
127
mHLA-DR recovery was associated with increased risk of secondary • Landelle C, Lepape A, Voirin N, et al. Low monocyte human
infections in a mixed ICU population and in trauma patients. 87,88,120,128-130 leukocyte antigen-DR is independently associated with nosoco-
IFN-γ can reverse impaired antigen presentation by monocytes and mial infections after septic shock. Intensive Care Med. 2010;36:
this effect can be indirectly estimated by measuring HLA-DR expression 1859-1866
on the cell membrane and in an experimental model of sepsis IFN-γ • Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus
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restored HLA-DR expression on antigen presenting cells. A double- reactivation in critically ill immunocompetent patients. JAMA.
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blind, placebo-controlled clinical trial of 416 patients with severe inju- 2008;300:413-422.
ries suggested that subcutaneous administration of recombinant IFN-γ • Meisel C, Schefold JC, Pschowski R, et al. GM-CSF to reverse
may be effective in diminishing the risk of death due to infectious com-
plications, but another study evaluating IFN-γ in burn patients did sepsis-associated immunosuppression: a double-blind random-
133
ized placebo-controlled multicenter trial. Am J Respir Crit Care
not demonstrate a reduction in the incidence of nosocomial infections
or enhance survival. 134 Med. 2009;180:640-648.
Although G-CSF is a promising immunostimulant, results regarding • Meisel C, Schefold JC, Pschowski R, et al. Granulocytemacrophage
clinical effectiveness in severe sepsis/shock are conflicting. In a recent colony-stimulating factor to reverse sepsis-associated immu-
trial, 164 patients with septic shock were randomly assigned to placebo nosuppression: a double-blind, randomized, placebo-controlled
or G-CSF treatment for 10 days. Analysis failed to demonstrate any multicenter trial. Am J Respir Crit Care Med. 2009;180:640-648.
benefit from G-CSF treatment on mortality. In line with these results • Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms
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one recent review suggested that future studies should be conducted to in sepsis. Nature Rev Immunol. 2008;8:776-787.
determine both optimal dosing regimens as well as safety and that this • Schefold JC, Hasper D, Reinke P. Consider delayed immunosup-
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treatment then could be further studied in prospective trials. 137 pression into the concept of sepsis. Crit Care Med. 2008;36(11):3118
In a recent meta-analysis, a total of 12 placebo-controlled random- • van der Poll T, Opal SM. Host-pathogen interactions in sepsis.
ized controlled trials (RCTs; n = 2380 patients) investigating the clinical Lancet Infect Dis. 2008;8:32-43.
effects of G-CSF (n = 8 RCTs) and GM-CSF (n = 4 RCTs) in patients • Venet F, Chung CS, Kherouf H, et al. Increased circulating
with severe sepsis/septic shock were pooled for analysis. No significant regulatory T cells (CD4(+)CD25 (+)CD127 (−)) contribute to
difference in 28-day mortality (relative risk [RR] 0.93; 95% confidence lymphocyte anergy in septic shock patients. Intensive Care Med.
interval [CI] 0.79-1.11; p = 0.44) and in-hospital mortality (RR 0.97; 2009;35:678-686.
95% CI 0.69-1.36; p = 0.86) was observed when patients receiving
G-CSF or GM-CSF were compared to placebo-treated controls. Analysis
of G-CSF (n = 2044; 6 RCTs) or GM-CSF (n = 89; 3 RCTs) treatment
subgroups revealed no 28-day mortality benefit. However, patients REFERENCES
receiving G-CSF or GM-CSF therapy have a significantly increased rate
of reversal from infection (RR 1.34; 95% CI 1.11-1.62; p = 0.002). 138 Complete references available online at www.mhprofessional.com/hall

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