innovative therapies for sepsis

Innovative Therapies for SepsisSreenandh Krishnagopalan and R. Phillip DellingerSection of Critical Care Medicine, Rush Medical College, Rush-Presbyterian-St. Luke’s MedicalCenter and Cook County Hospital, Chicago, Illinois, USA

Abstract Sepsis and septic shock continue to be a major cause of morbidity and mor-tality. Despite numerous advances in the supportive care of patients with sepsis,the overall mortality has changed little in the past 20 years. Many innovativetherapies have been attempted in the field of sepsis, primarily aimed at stoppingthe cycle of cytokine activation which is part of the systemic inflammatoryresponse. Therapies have also targeted other molecular mediators of inflamma-tion and coagulation. Despite encouraging preliminary preclinical results, mostof the early trials in sepsis research have failed to offer hope of improving survivalwith the use of these innovative therapies. Postulated reasons for the failure ofclinical trials include the disparity between animal models and clinical reality,the heterogeneous nature of patient populations and sepsis, and the complexityof the inflammatory cascade. On a more hopeful note, three recent trialsassessing corticosteroids, anti-tumour necrosis factor strategy and drotrecoginalfa (rhAPC), respectively, have proclaimed positive results. However, only thedrotrecogin alfa trial has been peer reviewed and published.

CURRENT OPINION BioDrugs 2001; 15 (10): 645-6541173-8804/01/0010-0645/$22.00/0

© Adis International Limited. All rights reserved.

1. Epidemiology of Sepsis

Sepsis and septic shock continue to be a majorcause of mortality and morbidity, with recent esti-mates indicating approximately 500 000 cases ofsepsis in the US every year.[1] There has been anincrease in the incidence of sepsis over the past 20years; this number is expected to continue to rise,primarily because of an aging and increasingly im-munocompromised patient population, the increas-ing use of invasive medical interventions and therising incidence of drug-resistant organisms.

Over the past 20 years our understanding of thepathophysiology of sepsis has become increasinglysophisticated, with dramatic discoveries comingfrom the application of new techniques in molecu-lar biology. The hope has been that with our delin-eation of the molecular basis of sepsis we would beable to interrupt the disease process by use of spe-cifically targeted interventions. However, the‘Holy Grail’ of effective antisepsis therapy hasremained elusive, with some advances but more

typically, major setbacks. The crude mortality forsepsis has been in the vicinity of 35%, a numberthat has not changed significantly over the past 20years,[1,2] despite the use of increasingly sophisti-cated supportive technologies.

In this article we review the various approachesto innovative therapy of severe sepsis and septicshock, reflecting on the past failures and also ex-ploring several newer interventions that show con-siderable promise. We performed a Medline searchusing the keywords sepsis, severe sepsis, sepsissyndrome, and septic shock and cross-referencingthese with human clinical trials. The results of thesearch were then manually reviewed and classified,focusing on larger prospective clinical trials.

2. The Sepsis Syndrome andthe Systemic InflammatoryResponse Syndrome

To understand the various innovative therapiesthat have been used in the treatment of sepsis, a

basic understanding of the pathophysiology isimportant. Sepsis is a clinical syndrome resultingfrom a systemic response of the body to infection.It is characterised and modulated by various pro-inflammatory and counter-regulatory anti-inflam-matory pathways. The pro-inflammatory compo-nent of this syndrome is thought to be associatedwith significant morbidity and mortality and hasbeen labelled the systemic inflammatory responsesyndrome (SIRS).[3,4] The pro-inflammatory re-sponse is intimately tied to the activation of thecoagulation and complement systems, the compos-ite of which puts organs at risk for injury and dys-function.

After an initial exposure to an infectious stimu-lus such as endotoxin from the cell wall of Gram-negative bacilli, the inflammatory cascade is initi-ated. Evidence from experimental studies in bothanimals and humans indicates that the most impor-tant early cytokines appear to be tumour necrosisfactor (TNF)-α and interleukin (IL)-1.[5-7] These inturn begin to initiate further players in the pro-inflammatory cytokine cascade, including IL-6(which is thought to be a marker of the severity ofthe inflammatory response but not directly injuri-ous), IL-8, IL-12 and interferon (IFN)-γ. The coag-ulation and complement systems are also activatedin the microcirculation.[8] A compensatory anti-inflammatory network is in turn initiated as thebody attempts to modulate the inflammation result-ing from the above mediators. Major players in theanti-inflammatory network include IL-10, IL-1receptor antagonist (IL-1ra), IL-6 and solubleTNFα receptor antagonist. In addition to thesecytokines, other global mediators of inflammationsuch as corticosteroids and endocrine hormonesalso are active in this milieu. The body’s ability tomodulate an overzealous pro-inflammatory re-sponse with increased adrenal release of steroidsmay also be overwhelmed. Recent research hasalso shed light on the role of nitric oxide in a mul-titude of biological processes, including a likelypivotal role in the haemodynamic profile of sep-sis.[9] The interplay of these pro- and anti-inflam-matory systems is important in the clinical mani-

festation of sepsis. The relative strength of theseopposing systems may be determined by the natureof the inflammatory stimulus, previous stimuli tothe host, and genetic variability.[10-12]

3. Clinical Trials in Sepsis: The Early Years

Given this basic understanding of sepsis, exper-imental and therapeutic interventions have beenaimed at different steps in this process, blockingpro-inflammatory factors but also attempting tobolster the anti-inflammatory mediators. Earlytrials featured steroid therapy as well as blockadetargeted toward endotoxin, TNFα, IL-1, plateletactivating factor (PAF), bradykinin, prostaglandinsand nitric oxide.

3.1 Anticytokine Therapies

3.1.1 Endotoxin as a TargetEndotoxin is a complex glycolipid found on the

cell walls of Gram-negative bacteria. It has longbeen known to be a powerful stimulator of the in-flammatory cascade and the major trigger in theseptic response to Gram-negative bacterial infec-tions, which are a leading cause of sepsis. It wouldbe reasonable to assume that therapies targetingthis molecule would be beneficial in limiting oreven preventing the initiation of the inflammatorycascade. The first clinical study examining theeffects of anti-endotoxin antibodies in humans wasperformed using polyclonal J5 antiserum. Prelimi-nary results suggested a 45% mortality reductionin patients with Gram-negative bacteraemia[13] andprevention of septic shock when given prophylac-tically in surgical patients.[14]

Because of the risk of transmission of virusesassociated with the use of polyclonal antiserum,monoclonal antibodies were subsequently devel-oped. These included E5, a murine monoclonal anti-body, and nebacumab (HA-1A), a mouse-humanhybrid monoclonal antibody. In addition to smallerstudies, two large clinical trials of E5 murinemonoclonal anti-endotoxin antibody have beenconducted, with 847 and 1102 patients, respec-tively.[15,16] Despite adequate power and large

646 Krishnagopalan & Dellinger

© Adis International Limited. All rights reserved. BioDrugs 2001; 15 (10)

numbers, these trials again failed to demonstrateany significant survival benefit.

Two large, multicentre phase III trials looked atthe effects of nebacumab, first in sepsis (543 pa-tients) and later in Gram-negative septic shock(2199 patients); no significant survival benefitwas demonstrated in either of these studies.[17,18]

3.1.2 Anti-Tumour Necrosis Factor (TNF) Strategiesand Early Anti-TNF StudiesTNFα is a 17.5kD protein released by various

inflammatory cells, and a plethora of experimentalevidence has pointed to this cytokine as an earlyinitiator of the inflammatory sepsis cascade. Mul-tiple large studies have been conducted targetingTNFα, in the hope that limiting the septic responseat this early level would attenuate the systemic in-flammatory response. Two major approaches havebeen taken in this regard: use of monoclonal anti-bodies to TNF and the use of fusion protein con-structs combining the extramembrane portion ofthe TNF receptor with the Fc fragment of a humanimmunoglobulin (Ig) G1 antibody. The fusionconstructs have used either p55 (type I) or p75(type II) TNF receptors.

Some of the original animal studies in sepsisdemonstrated a significant survival benefit withthe use of anti-TNF antibodies,[19,20] and smallinitial trials appeared to show possible benefit withpositive effects on the cytokine profiles of pa-tients with sepsis.[21] The North American SepsisTrial (NORASEPT) I examined a murine IgG1monoclonal antibody to TNF in 994 patients.[22]

Although there was no overall survival benefit,analysis of a prospectively defined subgroup of pa-tients with septic shock suggested an early survivalbenefit in patients treated with the higher doses ofthe drug. The International Sepsis Trial (INTER-SEPT) was a subsequent international multicentretrial involving a total of 564 patients, 420 of whomwere in septic shock.[23] This trial showed a trendtowards a survival benefit in patients treated withthe 3 mg/kg dose of the same murine IgG1 anti-TNF monoclonal antibody, but levels of statisticalsignificance were not reached.

NORASEPT II, one of the largest trials to beconducted in sepsis, enrolled more than 1900 pa-tients with septic shock, but in a great disappoint-ment to the medical community, failed to show anysignificant survival benefit with the use of murinemonoclonal antibodies to TNF.[24]

A study using a construct combining the Fc por-tion of the human IgG1 antibody and the ex-tramembrane portion of the type II (p75) TNF re-ceptor was conducted with 141 patients with septicshock. Not only was no survival benefit seen withthe use of this compound, but an increase in mor-tality was observed with the use of the higher dose(1.5 mg/kg).[25] A similar soluble construct ap-proach using the type I (p55) receptor has beentested in two large multicentre, randomised, con-trolled trials (with 498 and 1342 patients, respec-tively); no significant survival benefit was demon-strated in either trial.[26,27]

3.1.3 Interleukin-1−Targeted StudiesIL-1 has also been identified as an early player

in the pathogenesis of sepsis, and strategies tar-geting this cytokine have mainly focused on block-ade of the IL-1 receptor. One phase II and two largephase III trials of IL-1ra failed to demonstrate anysurvival benefit with the use of this agent in sepsisor septic shock.[28-30]

3.2 Anti-Inflammatory Agents

3.2.1 CorticosteroidsCorticosteroids are powerful inhibitors of sys-

temic inflammation both in humans and in ani-mals. Numerous studies, with varying results, havebeen conducted to assess the viability of usingthese agents in attenuating the overzealous in-flammation associated with the septic response.Several randomised trials were conducted in the1980s,[31,32] but failed to demonstrate the efficacyof corticosteroid therapy. Corticosteroids weregiven early, for a short period of time, and at highdoses. However, interest has been maintained inthe potential role of corticosteroids in sepsis, anda series of smaller studies in typhoid fever,[33] men-ingitis[34] and pneumocystis infections[35] seemedto suggest a possible beneficial role. Recently, two

Innovative Therapies for Sepsis 647


small randomised, double-blind studies usingstress doses of corticosteroids for more prolongedperiods have shown some promise.[36,37] Theseencouraging results may relate to the targeting of‘relative adrenal insufficiency’, i.e. failure toachieve an appropriate boost in cortisol levelsindependent of baseline levels.

3.2.2 Prostaglandin InhibitionIbuprofen is a potent inhibitor of cyclo-oxygen-

ase, with anti-inflammatory effects stemming fromthis effect on prostaglandin metabolism. Despitesuccess in animal studies,[38-40] and two smallerrandomised trials suggesting some benefit,[41,42] alarge multicentre, randomised, double-blind studyof ibuprofen in sepsis failed to demonstrate signif-icant overall survival benefit.[43]

3.3 Other Therapies

3.3.1 Platelet Activating Factor (PAF)An initial trial using a PAF receptor antagonist,

BN 52021 (ginkgolide B), in 262 patients failed toshow overall benefit but suggested a possible bene-fit in a subset of patients with Gram-negative sep-sis.[44] A large prospective, randomised trial of 608patients with severe Gram-negative sepsis was sub-sequently undertaken. This trial, however, failedto demonstrate significant survival benefit in thissubset of patients.[45] A phase II trial of anotherPAF receptor antagonist, BB-882, also did notshow any benefit in patients with sepsis.[46]

3.3.2 Nitric Oxide InhibitionOver the past 10 years, the role of nitric oxide

in many physiological processes has come to light,including a pivotal role in the haemodynamicmanifestations of severe sepsis and septic shock.[9]

Nitric oxide is a potent vasodilator and a crucialplayer in the low systemic vascular resistance as-sociated with sepsis and septic shock. After dem-onstrated promise in small trials,[47] a phase IIIprospective, multicentre, randomised, placebo-controlled trial of a nitric oxide synthase inhibitor,N(G)-methyl-L-arginine hydrochloride, was endedprematurely because of increased mortality in thetreatment group.[48]

3.3.3 Bradykinin AntagonistsKinins such as bradykinin and kallidin are pep-

tide mediators that have been implicated in the pro-inflammatory cascade of sepsis. A phase II clinicaltrial of deltibant (CP-0127), a bradykinin antago-nist, in 504 patients failed to reduce mortality inseptic patients at 7 or 28 days, but post hoc analysissuggested improvement in a subset of patients withSIRS and Gram-negative sepsis.[49] Further devel-opment of this drug has been abandoned.

3.3.4 ImmunostimulationInvestigations have also focused on amplifying

the immune response and relieving the ‘immuneparalysis’ that is seen in some patients with sepsis,using granulocyte colony-stimulating factor (G-CSF), a glycoprotein that increases neutrophilnumber and activity.[50-52] Although a large trial ofG-CSF in 756 patients with community-acquiredpneumonia showed a reduction of complicationsand decrease in progression to septic shock, otherresults have been mixed.[53] Similarly, attempts tomodulate the immune system by using IFNγ, a pro-inflammatory mediator, have shown promise insmaller trials.[54]

3.3.5 HaemofiltrationMany small trials have focused on the use of

continuous renal replacement therapies in patientswith sepsis, as experimental and clinical evidencehas demonstrated possible clearance of inflamma-tory mediators and complement by this method.Although preliminary results are promising, largerprospective, randomised trials are still needed be-fore this therapy should be used outside clinicaltrials.[55,56]

3.3.6 ImmunoglobulinsGiven that patients with sepsis have been found

to have serum Ig levels in the lower normal range,attention has focused on the use of intravenousimmunoglobulin (IVIG).[57,58] A large prospectivetrial of intravenous IgG in 653 patients who metpredetermined criteria for severity of illness (sepsisscore 12-27 and APACHE II score 20-35) failed todemonstrate any significant survival benefit. How-ever, trials that have focused on the use of IVIG in



subsets of patients with postoperative sepsis, orprophylactically in patients undergoing major sur-gery with a high risk for infections, have suggestedbenefit.[59,60]

4. Why the Failures?

Over the past 19 years, despite what had seemedto be remarkably promising therapeutic optionssupported by animal experimentation, and no shor-tage of effort, the battle against sepsis has beenlargely without significant victories. This is not al-together surprising when examined with the powerof hindsight. The failures of these trials have actu-ally been in a way enlightening, as they haveaided our understanding of the extremely com-plex nature of the inflammatory response in sepsis.They have also taught us some fundamental les-sons in the basic biological differences betweenthe real world of critically ill human patients andthe artificial conditions of animal models of dis-ease. Several common ideas have emerged fromthe past several years as analysis of these trials hasprogressed.[2,61,62]

4.1 Animal Models May Not AccuratelyPredict the Human Response

A consistent theme, and one that has causedmuch puzzlement in the assessment of the variousantisepsis compounds, is the finding of repeatedsuccess in attenuating the course of the disease innumerous animal studies, but failure to demon-strate such benefit when these therapies are as-sessed in large human trials. Although animalmodels are beneficial, the nature of experimentalresearch justifiably results in settings that are ar-tificial and often far removed from the realityof disease. The animals are usually healthy andyoung, and genetically identical, and the timing ofinitial microbial insult is known. This is in starkcontrast to the typical patients seen in the criticalcare setting. Although it is unlikely that our an-imal models can change substantially, these differ-ences need to be taken in to consideration whendesigning trials with regard to sample size andpower calculations.

4.2 Sepsis Is a Heterogeneous Syndrome

Much effort has been focused on the syndrome ofsepsis itself, which is the final common pathway re-sulting from the systemic inflammatory response.We have made little effort to differentiate the initi-ating insult in trials of sepsis, and consideration hasnot been given to classifying patients on the basisof the micro-organism involved. Some trials, suchas the trial of opebacan, a recombinant bacte-rial/permeability-increasing protein (rBPI21),[63]

have analysed the effects of the compound in thespecific setting of children with meningococcalsepsis and have suggested potential benefits in thisnarrow, selected patient subset.

An analysis of the microbial mediators in sepsisin the present day[1] reveals that the microbiologyis highly varied, with Gram-positive and Gram-negative organisms playing an equal role. It is lesslikely that therapies targeted at endotoxin wouldhave a demonstrable benefit in sepsis secondary tobacterial pathogens other than Gram-negative bac-teria. However, endotoxaemia has been reported inthe absence of Gram-negative infection,[64] postu-lated to be due to gut leakage.

4.3 The Inflammatory Response IsHighly Complex

The pro-inflammatory response of sepsis ischaracterised by a redundant cascade of pathways.Thus it appears that blockade of the pathway atone level may not be enough to attenuate the pro-inflammatory response, as alternative pathwaysmay exist, continuing to drive the inflammatoryresponse. Combinations of agents may need to beused to ensure adequate blockade of the sepsis cas-cade.

It is difficult to make assumptions based on an-imal studies as to when interventional agentswould be most effective. The time course of sepsisin animal experiments may be markedly differentfrom that seen in real clinical situations involvinghumans. It is possible that there is a narrow thera-peutic window in which therapies are effective, awindow which may be difficult to achieve given



the delay between the initial microbial insult andclinical presentation as well as the time from pre-sentation to diagnosis.

4.4 Patient Populations in the StudiesMay Be Too Heterogeneous

Patients have been entered into sepsis trials onthe basis of broad selection criteria, usually definedby the presence of SIRS due to infection (sepsis)and organ dysfunction due to sepsis (severe sepsis).Although stratification may be performed on thebasis of severity of illness score, patients are usu-ally not stratified by organ system of primary in-fection, specific bacterial pathogens involved,comorbid conditions or relative degree of inflam-matory response. All of these factors could poten-tially affect outcome. In addition, there appears tobe definite variability in the degree and type of in-flammatory response from patient to patient. Al-though some of this variability may be due to vari-ations in the initial disease process, increasingevidence points to genetically determined differ-ences in individual cytokine responses to incitingagents.[10-12] In future, particular subsets of patientswho are at risk and who are likely to respond tospecific therapies may be defined, based on cyto-kine profiles and the presence of gene polymor-phisms, before the initiation of therapeutic inter-ventions.

5. Clinical Trial Results in theNew Millennium

Much has been learned in the previous era oftrials in the treatment of sepsis. The past year hasbeen remarkable in that several trials have beencompleted which, it is hoped, may herald a newphase in our therapy of sepsis and septic shock.

5.1 Anticoagulant Therapy

Increasing evidence has pointed to the role ofthe microcirculation and widespread dysfunctionat the endothelial cell level. Thus, widespread ac-tivation of the coagulation system leading tomicrothrombotic events may be partly responsible

for the maintenance of sepsis physiology and theresulting organ dysfunction. Newer therapies aretargeting mediators of endothelial dysfunction andthe consumptive coagulopathy of sepsis.

5.1.1 Antithrombin IIIAn early and prolonged decrease in anti-

thrombin (AT) III levels has been repeatedly dem-onstrated in patients during sepsis-induced dis-seminated intravascular coagulation and in thesystemic inflammatory response. Supplementationwith exogenous AT III has thus been postulatedto be of benefit.[65] Four randomised, placebo-con-trolled trials of AT III in sepsis have been per-formed, and although no significant survival ben-efits were demonstrated, a trend towards a possiblesurvival benefit was suggested.[65-68] A recentmulticentre phase III trial, however, failed to con-firm benefit in adult sepsis (Steven Opal, personalcommunication).

5.1.2 Tissue Factor Pathway InhibitionTissue factor appears to mediate microvascular

thromboses and endothelial activation, two con-tributory factors in the development of multiple or-gan failure associated with severe sepsis. Tissuefactor pathway inhibitor is an endogenous mole-cule that inhibits the coagulation cascades associ-ated with tissue factor.[69] Animal studies haveshown promise in reducing mortality.[70,71] A largephase III study is in progress.

5.1.3 Activated Protein CActivated protein C has been found to have anti-

thrombotic, profibrinolytic and anti-inflammatoryproperties, and it is likely that the protein C defi-ciency often seen in sepsis leads to thrombin gen-eration in the microvasculature, contributing to en-dothelial dysfunction and an increase in theinflammatory response.[72] A trial of drotrecoginalfa (recombinant human activated protein C;rhAPC) in 1690 patients in 11 countries was re-cently conducted. In a remarkable, positive note insepsis treatment, this trial demonstrated a statisti-cally significant 19.43% reduction in relativerisk of death at 28 days with no significant in-crease in morbidity other than a slight increase in



bleeding (p = 0.06) noted in the drotrecogin alfa-treated group.[73,74]

5.2 Return to Corticosteroid Therapy

A recently completed French trial assessing cor-ticosteroids in patients with sepsis and relativeadrenal insufficiency (defined as <10 μg/dl in-crease in cortisol level in response to corticotropinstimulation testing) has been presented as an ab-stract reporting a reduction in mortality associ-ated with corticosteroid treatment.[75] In thistrial the dosage of corticosteroid was 50mg ofhydrocortisone every 6 hours in addition to 50μgof fludrocortisone daily for 7 days.

5.3 Re-Evaluation of Anti-TNF Therapy

Although a study conducted using the Fab2 frag-ments of a murine IgG3 monoclonal antibody toTNFα (afelimomab) in 122 patients with sepsisfailed to show any significant survival benefit inan intent-to-treat analysis, retrospective analysissuggested a benefit in patients with high (>1000ng/L) circulating IL-6 levels.[76] A larger trial withthis compound failed to verify a significant effectin this subgroup, although survival was 3.7%greater in the treatment arm.[77] A third trial alsofailed to achieve unadjusted statistical significancein patients with sepsis with circulating IL-6 >1000ng/L (the population of interest); however, a pvalue of <0.05 was achieved in all patients enrolledwith an intent-to-treat analysis as well as with alinear regression-adjusted analysis (SOFA predic-tion of mortality) in patients with an IL-6 level>1000 ng/L.[78]

Zeni and colleagues[61] showed that if all com-pleted trials in sepsis are combined (including allagents), there is a statistically significant 3% over-all reduction in 28-day all-cause mortality. Thelargest groups of patients in this analysis had re-ceived anti-TNF and anti-IL-1 therapy. A morerecent review of the trials using antibodies to TNFsuggests a small but statistically significant reduc-tion in 28-day all-cause mortality.[79] Interestingly,both anti-TNF and anti-IL-1 therapies are now ap-proved by the US Food and Drug Administration

to treat the inflammation of Crohn’s disease andrheumatoid arthritis.[80]

5.4 PAF Inhibition Revisited

The results of a phase II trial of PAF acetyl-hydrolase, a direct antagonist of PAF, have beenrecently presented in an abstract.[81] This study wasin a mixed population of patients with trauma orsevere sepsis, and the authors reported a significantreduction in 28-day mortality as well as a decreasein the incidence of acute respiratory distress syn-drome in all patients. The survival benefit was evenstronger when the subset of patients with severesepsis was examined alone.

6. Conclusion: Hope for the Future

Sepsis remains one of the leading causes of mor-tality. Despite an increasingly sophisticated under-standing of the pathophysiology, multiple largetrials consistently failed to show definitive benefitin reducing mortality from this deadly illness. Aswith all advances in medicine, it is inevitable thatthere should be setbacks and reappraisal beforemajor breakthroughs are achieved. The numeroustrials have in fact taught us valuable lessons in trialdesign and sepsis physiology and suggested moreclear-cut avenues for investigation. As our know-ledge of the individualised reaction to bacterial in-sult grows, the more accurately we can matchtherapies to particular patients. The apparent re-cent success of trials using corticosteroids (await-ing peer review) and drotrecogin alpha (FDA ap-proval pending), as well as a potentially beneficialeffect of anti-TNF therapy (also under peer re-view), should represent a new phase in sepsistherapy, and new therapeutic trials incorporatingthe lessons that we have learned are likely to revealadditional useful agents in future.

Acknowledgements

Dr Dellinger has received speaker honoraria or consult-ant fees from Bayer (anti-tumour necrosis factor antibody,no longer under development), Synergon (interleukin-1 re-ceptor antagonist, no longer under development for the treat-



ment of sepsis), Knoll (anti-tumour necrosis factor antibody)and Lilly [drotrecogin alpha (rhAPC)].

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Correspondence and offprints: Dr R. Phillip Dellinger, Sec-tion of Critical Care Medicine, Rush-Presbyterian-St. Luke’sMedical Center, Room 979 Jelke, 1653 West Congress Park-way, Chicago, IL 60612-3833, USA.



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