Fumeaux, Thierry

Pugin, Jérôme

RERO DOC Digital Library

Intensive Care Med (2006) 32:1106–1108DOI 10.1007/s00134-006-0205-7 E D I T O R I A LThierry FumeauxJérôme Pugin Is the measurement of monocytes HLA-DRexpression useful in patients with sepsis?Received: 20 April 2006Accepted: 20 April 2006Published online: 2 June 2006© Springer-Verlag 2006This editorial refers to the article available at:http://dx.doi.org/10.1007/s00134-006-0204-8T. FumeauxHôpital de Nyon/GHOL, Intensive Care, Internal Medicine,1260, Nyon, SwitzerlandJ. Pugin ()University Hospital of Geneva, Intensive Care,1211, Geneva 14, Switzerlande-mail: jerome.pugin@medecine.unige.chTel.: +41-22-3729236Fax: +41-22-3729105Leukocytes undergo significant reprogramming in patientswith sepsis [1]. Compared with monocytes from healthysubjects, monocytes from patients with severe infectionslose their capacity to mount a pro-inflammatory responseafter stimulation with bacterial products. Not only dothey produce less pro-inflammatory cytokines, they alsoincrease their production of anti-inflammatory mediatorsand receptor antagonists, such as the monocyte de-activating interleukin (IL)-10 and IL-ra [2]. This gives theplasma a dominant “anti-inflammatory” flavor [3]. It hasbeen proposed that this phenomenon is a compensatoryreaction to the initial inflammatory response [4]. Webelieve that this is an essential adaptive systemic responseaimed at concentrating the inflammatory response at thesite of infection, in the organs [5]. A decreased surfaceexpression of major histocompatibility class II moleculeswas also described in circulating monocytes from patientswith sepsis, as well as in other critically ill patients. This isassociated with an impaired antigen presentation capacity.The association of a decreased HLA-DR expressionand a blunted pro-inflammatory cytokine production bymonocytes is also known as “immunoparalysis” [6]. Themolecular mechanisms of HLA-DR downregulation at thesurface of monocytes from critically ill patients are nowbetter understood. HLA-DR production is impaired, andis retained intracellularly [7, 8, 9, 10]. Interestingly, thismonocyte phenotype can be reversed by the treatment ofseptic patients with interferon-γ or granulocyte–monocytecolony-stimulating factor [11, 12, 13]. Unfortunately,these studies were not powered to demonstrate an im-provement in survival in patients with severe sepsis,nor did they show a convincing decrease in the rate ofsecondary infections.Monocyte HLA-DR expression has been reported in40 studies in a total of over 1,400 critically ill patients [14,15]. An association between low HLA-DR expression andbad outcome was found in many of these studies, but notin all. Importantly, the populations of critically ill patientsstudied were quite diverse: medical, postsurgical, burns,transplant, and trauma patients, as well as patients withsepsis of various degrees of severity. The outcome vari-ables measured were also numerous, including rate of sec-ondary infections, development of shock, organ dysfunc-tion and death. It has therefore been impossible to aggre-gate data from the different studies and to draw a defi-nite conclusion as to whether HLA-DR measurement of-fers a significant benefit to the critically ill patient.In a study reported in this issue of Intensive CareMedicine, Monneret et al. measured the level of expres-sion of monocyte HLA-DR and its evolution with time in93 patients with septic shock [16]. Persisting low HLA-DRvalues—defined as < 30% positive monocytes—at day3–4 after ICU admission identified a population of patientswith a remarkably high mortality rate. Low HLA-DR wasan independent factor by multivariate analysis and wasfound to be a better predictor of mortality than SAPS IIand SOFA scores. In the absence of a specific interventionon HLA-DR expression, it is impossible to say whether1107low HLA-DR is a marker or a “mediator” of poor outcomein patients with septic shock. Monocyte HLA-DR levelsmay at best shed some light on the pathogenesis of im-mune dysfunction of critically ill patients. In no case willthis marker—as many other markers or scores of severi-ty—help the clinician to make radical decisions, such aswhether to withhold or withdraw treatments, for example.Monocyte HLA-DR expression is, however, becomingan easy and robust marker of the immune dysfunction ofcritically ill patients. It could be used in the future bothfor the detection of immune paralysis and as a usefulmonitoring tool for interventions in immune-suppressedcritically ill patients.This study reminds us of the three essential stepsnecessary to define a biological marker as a useful markerin our daily ICU practice. Firstly, the analytical conditionsof the test must be optimized, standardized and madereproducible. This has been a problem for many yearswith the measurement of HLA-DR expression. Incon-sistent results rendered comparisons between centersvirtually impossible. A kit for the quantification of themean expression of HLA-DR in circulating monocytesis now commercially available, which has very signifi-cantly decreased intra- and inter-assay variability [17].It requires access to a flow cytometer, however, and istherefore not exactly a simple bedside test. Monneret et al.measured HLA-DR with a non-commercial but accurateand reproducible method [18]. Interestingly, HLA-DR wassignificantly associated with outcome when these authorsexpressed results as % positive monocytes, but not whencell fluorescence was measured as “mean fluorescence in-dex (MFI)”. Although there is no clear explanation for thisfinding, this might only be due to an insufficient number ofpatients to achieve significant results with MFI. It wouldprobably now be important to compare the method usedby Monneret et al. with that of a commercially availablequantification kit for HLA-DR expression with regard totheir respective values as a prognostic marker.Secondly, the parameter should be tested in nor-mal subjects and prospectively in patients with well-characterized pathological conditions over time and withwell-defined outcomes. This step is essential to deter-mine normal values and also significant cut-off values atgiven time points during the course of the disease. Thestudies should be powered such that one can rely withsufficient confidence on the findings. HLA-DR expressionin critically ill patients is a prototypical situation wherethe studies are lacking that might establish indisputableconfidence in this marker in the clinical arena. The studyby Monneret et al. does, however, add a piece to thisedifice and is quite satisfying in this regard. The authorsincluded a fairly homogeneous population and a rea-sonable number of septic shock patients surviving after48 h, measured HLA-DR at several time points during thecourse of the disease, and determined a robust outcome,mortality. A methodological weakness of this study is itsmonocentric design, preventing testing of the inter-centerreproducibility of the results. Furthermore, their findingsnow need to be independently validated in another cohortof similar patients.The final and important step is the application of thetest in “impact studies”. No clinician wants another prog-nostic marker to test at the bedside without knowing whathe has to do with the results. Measuring this parametershould potentially allow the clinician to modify the careand ideally the outcome of his patient.As said earlier, it is not conceivable that low HLA-DRon day 3 or 4 will be used by the clinician to take dras-tic decisions, despite its good prognostic value. However,the results from this study permit identification of a popu-lation of patients with septic shock that have an increasedrisk of mortality, with an accuracy that is better than sever-ity scores. It is very likely that monocyte HLA-DR expres-sion persisting at low values at day 3 or 4 after the onsetof septic shock will identify patients with a persistent im-mune dysfunction. These patients are probably those whofail to clear out their primary bacterial infection and thoseat risk of acquiring lethal secondary infections. Therefore,the identification of these patients might be valuable toreinitiate infectious work-ups, optimize the source control,and possibly modify the antibiotic therapy. This test mayalso prove very useful to select patients in future interven-tion trials who could profit from immunomodulatory treat-ments. Although promising as a future tool for the careof the critically ill patient, monocyte HLA-DR expressionremains an investigational parameter, still has to be fullyvalidated, and needs to find its niche before it is widelyused.References1. Cavaillon JM, Adrie C, Fitting C Adib-Conquy M (2005) Reprogramming ofcirculatory cells in sepsis and SIRS. JEndotoxin Res 11:311–3202. Cohen J (2002) The immunopathogene-sis of sepsis. Nature 420:885–8913. Cavaillon JM (2002) “Septic plasma”:an immunosuppressive milieu. Am JRespir Crit Care Med 166:1417–14184. Bone RC (1996) Sir Isaac Newton,sepsis, SIRS, and CARS. Crit Care Med24:1125–11285. Munford RS, Pugin J (2001) Normalresponses to injury prevent systemicinflammation and can be immunosup-pressive. Am J Respir Crit Care Med163: 316–32111086. Volk HD, Reinke P, Docke WD (2000)Clinical aspects: from systemic inflam-mation to ’immunoparalysis’. ChemImmunol 74:162–1777. Pangault C, Le Tulzo Y, Tattevin P,Guilloux V, Bescher N, Drenou B(2006) Down-modulation of granulo-cyte macrophage-colony stimulatingfactor receptor on monocytes duringhuman septic shock. Crit Care Med34:1193–12018. Le Tulzo Y, Pangault C, Amiot L, Guil-loux V, Tribut O, Arvieux C, Camus C,Fauchet R, Thomas R, Drenou B (2004)Monocyte human leukocyte antigen-DRtranscriptional downregulation by cor-tisol during septic shock. Am J RespirCrit Care Med 169:1144–11519. Pachot A, Monneret G, Brion A,Venet F, Bohe J, Bienvenu J, Mougin B,Lepape A (2005) Messenger RNAexpression of major histocompatibilitycomplex class II genes in whole bloodfrom septic shock patients. Crit CareMed 33:31–38 discussion 236–23710. Fumeaux T, Pugin J (2002) Roleof interleukin-10 in the intracellularsequestration of human leukocyteantigen-DR in monocytes during septicshock. Am J Respir Crit Care Med166:1475–148211. Nierhaus A, Montag B, Timmler N,Frings DP, Gutensohn K, Jung R,Schneider CG, Pothmann W, Bras-sel AK, Schulte Am Esch J (2003)Reversal of immunoparalysis by recom-binant human granulocyte-macrophagecolony-stimulating factor in patientswith severe sepsis. Intensive Care Med29:646–65112. Docke WD, Randow F, Syrbe U,Krausch D, Asadullah K, Reinke P,Volk HD, Kox W (1997) Monocyte de-activation in septic patients: restorationby IFN-gamma treatment. Nat Med3:678–68113. Nakos G, Malamou-Mitsi VD,Lachana A, Karassavoglou A, Kit-siouli E, Agnandi N, Lekka MF (2002)Immunoparalysis in patients withsevere trauma and the effect of inhaledinterferon-gamma. Crit Care Med30:1488–149414. Spittler A, Roth E (2003) Is monocyteHLA-DR expression predictive forclinical outcome in sepsis? IntensiveCare Med 29:1211–121215. Tschoeke SK, Moldawer LL (2005)Human leukocyte antigen expression insepsis: what have we learned? Crit CareMed 33:236–23716. Monneret G, Lepape A, Voirin N,Bohé J, Venet F, Debard AL, Thizy H,Bienvenu J, Gueyffier F, Vanhems P(2006) Intensive Care Med DOI10.1007/s00134–0204-817. Docke WD, Hoflich C, Davis KA,Rottgers K, Meisel C, Kiefer P,Weber SU, Hedwig-Geissing M,Kreuzfelder E, Tschentscher P, Nebe T,Engel A, Monneret G, Spittler A,Schmolke K, Reinke P, Kunz D (2005)Monitoring temporary immunodepres-sion by flow cytometric measurementof monocytic HLA-DR expression:a multicenter standardized study. ClinChem 51:2341–234718. Monneret G, Elmenkouri N, Bohe J,Debard AL, Gutowski MC, Bienvenu J,Lepape A (2002) Analytical require-ments for measuring monocytic humanlymphocyte antigen DR by flow cytom-etry: application to the monitoring ofpatients with septic shock. Clin Chem48:1589–1592

Is the measurement of monocytes HLA-DR expression useful in patients with sepsis?

http://doc.rero.ch/record/311197/files/134_2006_Article_205.pdf

Is the measurement of monocytes HLA-DR expression useful in patients with sepsis?

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library