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Baltimore, MD
Dr. Napolitano is Professor of Surgery, University of Maryland School of Medicine.
Correspondence to: Lena M. Napolitano MD, FCCP, Professor of Surgery, University of Maryland School of Medicine, 10 North Greene St, Room 5C-122, Baltimore, MD 21201; e-mail: lnapolitano{at}smail.umaryland.edu
The colony-stimulating factors (CSFs) comprise a group of cytokines that are central to the hematopoiesis of blood cells, as well as to the maintenance of homeostasis and overall immune competence. This group consists of the macrophage-CSF (M-CSF), granulocyte-CSF (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and multi-CSF (interleukin [IL]-3). M-CSF and G-CSF are relatively lineage-specific, having a role in the proliferation, differentiation, and survival of macrophages, neutrophils, and their precursors. In contrast, GM-CSF and multi-CSF function at earlier stages of lineage commitment regulating the expansion and maturation of primitive hematopoietic progenitors.1 GM-CSF and G-CSF are naturally occurring cytokines that stimulate the production and antibacterial function of both neutrophils and monocytes.
Neutrophils, monocytes, and tissue-based macrophages are major cellular components of the innate immune system, which represents the initial line of host defense against invading pathogens in bacterial infection. In the past few years, both G-CSF and GM-CSF have received increasing attention as potential adjunctive immunomodulatory agents for the treatment of infectious diseases.2 Studies conducted in vitro and in vivo have shown that G-CSF and GM-CSF can augment the functional antimicrobial activities of neutrophils, and also can up-regulate multiple antimicrobial mechanisms in monocytes and macrophages. Studies conducted in animal models have shown the potential use of each of these cytokines for the treatment of infections caused by a variety of bacterial, fungal, and parasitic diseases.
Several studies and metaanalyses have addressed the clinical applications of CSFs to treat or prevent neutropenia. Guidelines have been developed to foster the appropriate use of CSFs. The clinical applications of the CSFs include primary febrile neutropenia prophylaxis, secondary febrile neutropenia prophylaxis, the treatment of febrile neutropenia, the support of dose-dense chemotherapy regimens, use in patients with leukemia and myelodysplastic syndromes, utility in stem cell transplantation, and use in elderly and pediatric patients.3 It should be noted, however, that although CSF use was associated with a significant reduction in the number of documented infections in these studies, CSFs did not reduce infection-related mortality.456
Therapy with CSFs has been extended beyond their use in accelerating myeloid cell recovery to take advantage of their immune function-enhancing properties.7 The potential ability to augment the activity of the innate immune system has increased dramatically during the past 2 decades. Both G-CSF and GM-CSF have received increasing attention as potential adjunctive agents for the treatment of infectious diseases. In various animal models of infection, therapeutic administration of each of these cytokines has been shown to enhance pathogen eradication and to decrease morbidity and/or mortality. However, variable therapeutic efficacy has been reported in the clinical trials conducted to date.8
In addition to ongoing investigation in adults, two strategies have been adopted for exploring whether CSFs can provide clinical benefit for preterm infants. The first strategy has investigated their use as a treatment to improve outcome in established systemic infection, especially when complicated by a low neutrophil count. The alternative strategy has been to use CSFs prophylactically, to prevent sepsis prospectively through the stimulation of neutrophil production and bactericidal function. A Cochrane Database Systematic Review9 examined the efficacy and safety of therapy with G-CSF or GM-CSF in newborn infants. The results of seven treatment studies of 257 infants with suspected systemic bacterial infection and three prophylaxis studies comprising 359 neonates were analyzed. There was no evidence that the addition of G-CSF or GM-CSF to antibiotic therapy in preterm infants with suspected systemic infections reduced the immediate all-cause mortality rate. This group concluded that there is currently insufficient evidence to support the introduction of either G-CSF or GM-CSF into neonatal practice, either as a treatment of established systemic infection to reduce resulting mortality, or as prophylaxis to prevent systemic infection in high-risk neonates. No toxicity was reported with CSF use in any study included in this review. The limited data suggesting that CSF treatment may reduce mortality when systemic infection is accompanied by severe neutropenia should be investigated further in adequately powered trials that recruit a sufficient number of infants infected with organisms that are associated with a significant mortality risk.
G-CSF differs from GM-CSF in its specificity of action on developing and mature neutrophils, its effects on neutrophil kinetics, and its toxicity profile. The toxicity profile of recombinant GM-CSF is consistent with the priming of macrophages for increased formation and the release of inflammatory cytokines, whereas recombinant G-CSF (rG-CSF) induces the production of antiinflammatory factors, such as IL-1 receptor antagonist and soluble tumor necrosis factor (TNF) receptors, and is protective against endotoxin-induced and sepsis-induced organ injury. The low toxicity of rG-CSF, the results of animal models of infection, and the extensive experience with neutropenic subjects have promoted clinical studies10 in nonneutropenic subjects, indicating that rG-CSF may be beneficial as adjunctive therapy for the treatment of serious bacterial and opportunistic fungal infections in nonneutropenic patients, including those with alterations in neutrophil function.
Studies have also begun to examine the endogenous host response to sepsis with time-dependent measurements of plasma CSFs. A prospective cohort study11 (n = 82) examined the circulating concentrations of G-CSF and GM-CSF during critical illness in four clinically defined groups, namely, septic shock (n = 29), sepsis without shock (n = 17), shock without sepsis (n = 22), and nonseptic, nonshock control subjects (n = 14). Plasma levels of G-CSF were greatly elevated in septic shock patients, correlated with the severity of illness measured by APACHE, but were not independently predictive of mortality or the development of multiple organ dysfunction. GM-CSF was rarely elevated, suggesting different roles for G-CSF and GM-CSF in human septic shock.
An additional single-center study12 documented that plasma GM-CSF levels in septic patients (n = 53) were statistically significantly depressed in patients who died compared with those who survived, who had levels that were comparable with those of healthy control subjects (n = 33). Low plasma GM-CSF levels in this study were associated with adverse consequences for septic patients. The measurement of GM-CSF levels in the plasma of septic patients merits further study for use as a prognostic marker and also to identify the type of immunotherapy the patient may benefit from.
GM-CSF is by far the hematopoietic growth factor that is most widely used for the augmentation of immune responses.13 Previous studies have suggested that GM-CSF may be useful in reversing the immune paralysis that has been described in the later stages of sepsis. Monocyte dysfunction has been shown to be associated with adverse consequences in septic patients. Therapy with the cytokine growth factor GM-CSF may be required for optimal monocyte function in these patients.
In this issue of CHEST (see page 2139), Rosenbloom and colleagues report the results of a prospective, randomized, placebo-controlled, unblinded trial of GM-CSF in 40 nonneutropenic patients with sepsis (ie, sepsis inflammatory response syndrome [SIRS] and a defined focus of infection with intent-to-treat antimicrobial agents). GM-CSF was administered as a continuous infusion for 72 h at a dose of 125 µg/m2. This treatment resulted in higher leukocyte counts, and a significantly greater rate of infection clinical and microbiologic cure/improvement, but no difference in mortality.
This is an important translational study that critically examines the effect of a biological modifier (ie, GM-CSF) on immune cell function in a prospective randomized study, and is an important contribution and advancement of our knowledge in this area of investigation. They documented that GM-CSF administration was associated with broad activation of the circulating leukocyte pool, with the up-regulation of the ß2-integrin adhesion molecule CD11b and human leukocyte antigen-DR, and the down-regulation of the adhesion molecule L-selectin.
We must recognize, however, that the study results are limited to the patient population, the GM-CSF dose, and the time period examined. This clinical study is unique in that it enrolled a high percentage of solid-organ transplant recipients. There were 7 solid-organ transplant recipients in the GM-CSF group (total, 18 recipients; 39%) and 8 solid-organ transplant recipients in the placebo group (total, 15 recipients; 53%), comprising about one third of the study population. Transplant patients with sepsis represent an exceedingly difficult patient population to study, since many prior sepsis trials have fully excluded these patients. Furthermore, many of these patients are still receiving immunosuppressive therapy, making their response to acute infection quite different from that of a healthy host. Therefore, it is extremely important to interpret the findings of this study in the context of the patient cohort enrolled.
Also, patients who were randomized had at least three SIRS criteria and a defined focus of infection with intent-to-treat with antimicrobial agents, thus representing "sepsis" patients. Patients with "severe sepsis" (defined as patients with sepsis and one or more organ failures) were not specifically studied, although a number of patients manifested organ failure as delineated in Table 1 of the study. The study excluded patients with "septic shock," which was defined as a "mean arterial pressure < 60 mm Hg or pressor dependence," but did not examine more accurate measurements of shock, including lactate level and base lactate deficit. The enrollment of patients with severe sepsis and septic shock should be considered in future trials.
Importantly, the conclusions of this study are limited to the timing, dose, and duration of the GM-CSF that was utilized. This study examined therapy with the continuous infusion of GM-CSF at an early time-point in the course of sepsis. It is unclear whether this is the optimal timing, optimal dose, and optimal route of administration, and future pharmacokinetic studies will be necessary to unravel these issues in critically ill patients.
Variability in the response to CSF therapy is likely related to a number of factors. Some investigators have documented that bacteria type alters the outcome with prophylactic G-CSF therapy during pneumonia. In a series of elegant animal studies14 using a rat model, G-CSF had fundamentally different and opposite effects during pneumonia with Escherichia coli vs that with Staphylococcus aureus. With E coli pneumonia, G-CSF therapy worsened oxygenation and increased bacteremia and mortality, whereas with S aureus pneumonia, G-CSF therapy improved oxygenation and decreased bacteremia and mortality. Thus, during S aureus pneumonia with low TNF levels, G-CSF therapy increased circulating neutrophil counts and bacterial clearance, resulting in less pulmonary injury and a decrease in the number of deaths. During E coli pneumonia with high TNF levels, G-CSF therapy paradoxically decreased circulating neutrophil counts, resulting in impaired bacterial clearance and worsened pulmonary injury and death. Bacterial species and the associated inflammatory mediator response can alter the outcome with prophylactic G-CSF therapy during pneumonia.
Similarly, other investigators have determined that G-CSF has different effects when comparing intravascular and extravascular models of sepsis.15 In contrast to extravascular infection (ie, intraperitoneal or intrabronchial), sepsis with intravascular E coli in canines and S aureus in rats may not provide a compartmentalized nidus of bacteria on which G-CSF-stimulated neutrophils can exert a beneficial antimicrobial effect. Extrapolated clinically, a proinflammatory agent like G-CSF may be most beneficial with sepsis that is related primarily to a compartmentalized extravascular site of infection.
The principal means of clearing G-CSF from the serum is by saturable binding to specific G-CSF receptors (G-CSFRs). The expression of the receptors that mediate G-CSF effects in neutrophils and monocytes/macrophages is also regulated by bacterial products, cytokines, and endogenous G-CSF levels, potentially accounting for the variable effects of G-CSF on the neutrophil functions of critically ill patients.16 Therefore, patients who have very high G-CSF serum/urine concentrations before the initial dosing of rG-CSF may have their G-CSFRs saturated before the initial G-CSF dose is administered. Some investigators speculate that if G-CSFRs are saturated with endogenous G-CSF, treatment with rG-CSF will add little or nothing to the granulocytopoietic effect, and patients are therefore unlikely to derive benefit from rG-CSF administration.17 This variability should be taken into account when designing future studies on the use of G-CSF in ICU patients.
Furthermore, genetic polymorphisms of the GM-CSF gene are known to exist and may play a pivotal role in the normal host response to infection and sepsis, and may determine an individual’s predisposition to infection and sepsis. A clinical study18 described novel polymorphisms of the GM-CSF gene in 113 children with atopic dermatitis and 114 control subjects. GM-CSF is known to be an important modulator of the function of skin Langerhans (dendritic) cells. Because dendritic cells initiate immune responses and thus are critical to the priming of an individual to potential allergens, we hypothesized that genetic factors controlling the activity of these cells determine an individual’s propensity to atopic dermatitis. The inheritance of a homozygous GM-CSF-677*C/C genotype was associated with the complete absence of severe atopic dermatitis within this cohort of children (p < 0.001). Furthermore, the odds ratio of having atopic dermatitis in children who were not of this genotype was 7.5 (95% confidence interval, 2.2 to 25). This study clearly documented that the GM-CSF genotype is an important genetic marker predicting an individual‘s predisposition to atopic dermatitis. Studies such as this in patients with health-care-associated infection and sepsis are lacking.
A note of caution, however. Activated neutrophils play a major role in the pathogenesis of ARDS and organ dysfunction, and the persistence of pulmonary neutrophilia is related to poor survival. It has been postulated that GM-CSF and G-CSF, which can promote the survival of neutrophils by delaying apoptosis, may prolong the inflammatory response. A recent study documented that concentrations of G-CSF in BAL fluid in patients with ARDS (n = 31) were significantly higher in nonsurvivors than survivors (p < 0.05).19 The higher levels of G-CSF in nonsurvivors, together with previous reports that recombinant G-CSF and GM-CSF occasionally induce acute lung injury, emphasize that the role of these mediators in pathogenesis needs to be elucidated.
So, is there a place for therapy with G-CSF and GM-CSF in nonneutropenic critically ill patients with infection and sepsis? Studies are still needed to identify the subset of patients who may benefit from G-CSF therapy. The resolution of these issues in the future will require carefully designed clinical studies with meticulous monitoring of immunologic parameters, such as the clinical study completed by Rosenbloom and colleagues. Because clinical experience with these immunomodulatory cytokines is relatively limited and currently investigational, additional controlled clinical trials will be necessary to define the specific indications for the administration of these cytokines in therapeutic regimens.
References
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