-/2- o,:;e. 1..)British Joumal of Surgel)' 1995, 82, 721-723

Leading articles

Adjuvant biologicaI response modifiers after majarsurgery or trauma

Few can dispute that the prophylactic use of antibiotics has had a major impact onthe incidence of infection following majar surgery and trauma. Nevertheless, withinthese clinical scen~io~evelopment of the sepsj~fresponse _its sequela of

concept or-augmenting endogenous antibacterial mechanisms by the administrationof non-antibiotic reagents has existed for some years and has had a somewhatchequered history. The use of monoclonal antibodies against endotoxin and/ortumour necrosis factor has a limited and, as yet, undefined role in the managementof patients with established sepsis; these antibodies have not been studied in thecontext of prophylaxis. However, two decades of research have considerablyexpanded our understanding of the immunophysiology of surgical and traumaticinjury, and recent trial data suggest that ibis knowledge might be ripe fortherapeutic exploitation1.z.

Central to these trials has be en the notion that injury, haemorrhage andendotoxin have profound effects on monocyte function and, in particular, result inthe release of a number of key cytokines, amongst which are prostaglandin (PG)EZ3 and transforming growth factor (TGF) p4. PGEz is principally an immuno-suppressive molecule which prevents the production and release of cytokines bythe Th 1 subclass of T helper lymphocytes whose products are, amongst others, theimportant cytokines interleukin (IL) 2 and interferon (IFN) }', the production ofboth of which is impaired following surgical or trauma tic injury. However, PGEz isalso capable of stimulating cells of the Th2 subclass whose cytokine productionprofile5 includes IL-4 and IL-10. These latter cytokines are inhibitory to Th1cytokine production and IL-10 is known to downregulate the expression of majarhistocompatibility complex (MHC) class 11 molecules on the surface of monocytesand T cells6. Similarly, TGF-p, while gene rally a downregulator of celIularprocesses, is also capable of stimulating7 the Th2 subset to produce IL-4 and IL-10.It has recently be en discovered that transcription of the gene for IL-10 isupregulated in peripheral blood mononuclear celIs folIowing majar resectionalsurgery (A. KIava et al., unpublished results), thereby adding another importantpiece to this jigsaw. Thus an explanation is beginning to emerge for thedownregulation of MHC class 11 expression, described by PoI k and bis colIeaguesfolIowing trauma tic injury8, and observations from the author's laboratory onmonocyte class II expression after majar resectional surgery9.

The therapeutic significance of these observations lies in the fact that theexpression of MHC class 11 antigens is a vital component of the antigen-presentingmechanism, whereby TcelIs facilitate specific antibody production by B celIs. It isal so a marker of monocyte activation and thus mar represent the capacity of amonocyte to engulf opsonized organisms. Since the downregulation of MHC class11 antigens correlates with clinical outcome and the development of infectionfolIowing surgery or trauma8.9, it seemed reasonable to attempt to augment thislevel clinicalIy by administering an agent that is able to do this in vitro, namelyIFN-y. Unfortunately, the first reported trial1O of this agent in traumatized patientsprovided supportive but not statisticalIy significant data. Treatment was withrecombinant human IFN-y (rHuIFN-y) or placebo in 213 randomized patients withtrauma at high risk of infection. The overalI mortality rate was significantly lowerin the treatment group but the incidence of serious infection requiring drainagewas not; it was concluded that a larger trial with a longer period of treatment wasjustified. The results of such a trial have recently been publishedl and haveprovided equalIy tantalizing results. Nine participating centres randomized 416patients to receive either placebo therapy or treatment with rHulFN-y for 21 daysor until hospital discharge. There were significantly fewer deaths related toinfection, as welI as fewer deaths overalI, in the treatment group. The number of

721

722 P. J. GUILLOU

early deaths (within 7 days) was the same in both groups, but the incidence of latedeaths in the treatment group was hall that of the placebo group. Since most latedeaths alter trauma.,are attributable to sepsis, IFN-y seemed to have had an impacton infective complications. Sadly, the data were dominated by findings from asingle centre which contributed a majority of patients to the study and statisticalanalysis could not eliminate an unidentifiable imbalance between the two arms asan explanation for the results. Taken alone, as with the earlier study by Polk eta[.1o, these data might be viewed as another inconclusive study of monocyteactivation procedures which demonstrate promising, though clinically marginal,advantages. However, a randomized clinical trial2 of the adjunctive administrationof another compound that significantly enhances macrophage microbicidal activity,namely poly-[1-6]-B-o-glucopyronasyl-[1-3]-B-o-glucopyranose (PGG-glucan), mustalso be taken into consideration. This was a dose-ranging study performed inpatients undergoing elective surgery who were considered at high risk ofdeveloping infection. Interestingly, there was a dose-related effect of adjuvanttreatment with PGG-glucan in diminishing the incidence of infection in thesepatients. These data are being used to design a prospective trial of PGG-glucan inpatients undergoing major resectional surgery. However, the significance of thisstudy is that, once again, the administration of a reagent that modifies the activityof phagocytic cells seemed to diminish infective complications in a group ofelective surgical patients al high risk of developing septic problems.

One of the difficulties with these trials is that, despite recruitment of moderatelylarge numbers of patients, the beneficial effects of the reagents often achievestatistical significance only at the most marginally acceptable level. This is probablya function of the multiplicity of factors that influence outcome after major traumaor surgery. However, it may al so be related to the fact that not all individualsrespond in an identical manner to these biologically active compounds. Forexample, in vitro stimulation of neutrophils with IFN-y or colony-stimulatingfactors consistently either downregulates or upregulates cell-surface receptors in aparticular individual, depending on the initiallevel of expression of the receptor. Ithas also recentlY be en demonstratedll that neutrophil activation early in thepostoperative period may be a harbinger of the development of surgical sepsis andthat such a response is al so related to the level of expression of certain receptorson the neutrophil surfacel2. The early studies, on the level of MHC class IIexpression on monocytes alter trauma, pointed to the fact that significant c.linicalmorbidity developed only in individuals whose post-trauma tic MHC class 11recovery was delayed or who did not recover at all; those whose MHC class 11levels fell and then rapidly returned to normal had an uneventful postoperativecourse8. Presumably the latter patients would not be expected to benefit clinicallyfrom therapy with IFN-y, and so the power to identify a beneficial effect of thistreatment might be improved if they could be identified and excluded from anytrial. Clearly this is impractical at present, but this example reinforces the point,made elsewherel3, that these variations in biological responses may need to beconsidered in future trials. Nevertheless, the clinical trials cited above appear, forthe first time, to provide some grounds for optimismo Perioperative biologicalresponse modifiers might be reaching the stage at which they can take their placealongside prophylactic antibiotics and improved critical caTe medicine in reducingserious morbidity and mortality alter majar surgery or trauma. Whether thecellular targets will be monocytes or neutrophils, or both, is unknown; greaterinsight is needed into the effects of trauma on these important components of theinflammatory response. In addition, the cellular and molecular basis of thevariability of the response merits further study, so that it may be taken intoaccount in the design of future trials of perioperative biological response modifiersin surgical practice.

P. J. GuillouAcademic Unit oi SurgeryDepartment oi Molecular MedicineClinical Sciences BuildingSt James's University HospitalLeeds LS9 7TFUK

British Joumal of Su'b'ery ] 995, 82, 721-723

723LEADING ARTICLES

1 Dries JR, Jurkovich GJ, Maier RV el al.Effect of interferon garnrna on infection-related death in patients with severeinjuries: a randornized, double-blind,placebo-controlled trial. Arch Surg 1994;129: 1031-41. .,

2 Babineau TJ, Hackford A, Kenler A el al.A phase 11 rnulticenter, double-blindrandornized, placebo-controlled study ofthree dosages of an irnrnunornodulator(PGG-glucan) in high-risk surgicalpatients.Arch Surg 1993; 129: 1204-10.

3 Grbic JT, Mannick JA, Gough DB,Rodrick ML. The Tole of prostaglandinE2 in irnrnune suppression followinginjury. Ann Surg 1991; 214: 253-63.

4 Miller-Graziano CL, Szabo G, Griffey K,Mehta B, Kodys K, Catalano D. Ro.le ofelevated rnonocyte transforrning growthfactor beta (TGF-P) production inposttraurna irnrnunosuppression. J ClinImmunol1991; 11: 95-102.

5 Betz M, Fox BS. Prostaglandin E2 inhibitsproduction of Th1 lyrnphokines but notof Th2 Iymphokines. J lmmunol 1991;146: 108-13.

6 de Waal Malefyt R, Haanen J, Spits H elal. lnterleukin-10 (IL-10) and vira.! lL-10strongly reduce antigen-specific húrnan Tcell proliferation by dirninishing theantigen-presenting capacity of rnonocytesvia downregulation of class 11 rnajorhistocornpatibility cornplex expression.J Exp Med 1991; 174: 915-24.

7 Ayala A, Lehman DH, Herdon CD,Chaudry IH. Mechanism of enhancedsusceptibility to sepsis Tollowinghaemorrhage; interleukin-10 suppressionof T -cell responses is mediated byeicosanoid-induced interleukin-4 synthesis.Arch Surg 1994; 129: 1172-8.

8 Hershman MJ, Cheadle WG, WellhausenSR, Davidson PR, Polk HC Jr. MonocyteHLA-DR antigen expression characterizesclinical outcome in the trauma patient.BrlSurg 1990; 77: 204-7.

9 Wakefield CH, Carey PD, Foulds S,Monson JRT, Guillou PJ. Changes inmajor histocompatibility complex class 11expression in monocytes and T cells ofpatients developing infection aftersurgery. Br 1 Surg 1993; 80: 205-9.

10 Polk HC Jr, Cheadle WG, Livingston DHet al. A randomized prospective clinicaltrial to determine the efficacy ofinterferon-y in severely injured patients.Am 1 Surg 1992; 63: 191-6.

11 'wakefield CH, Carey PD, Foulds S,Monson JRT, Guillou PJ. Polymorpho-nuclear leukocyte activation. An earlymarker of the postsurgical sepsisresponse.Arch Surg 1993; 128: 390-5.

12 Wakefield CH, Carey PD, Foulds S,Monson JRT, Guillou PJ. Surgery andthe release of a neutrophil Fc-¡ receptor.Am 1 Surg (in press).

13 Guillou PJ. Biological variation in thedevelopment of sepsis after surgery ortrauma. Lancet 1993; 342: 217-20.

British Joumal of Surgery 1995, 82, 721-723