Immune monitoring in intensive care patients

Transcription

1 28th General annual Meeting of the Belgian Hematological Society Immune monitoring in intensive care patients Guillaume Monneret Head Cellular Immunology Unit Hôp. E. Herriot-Hospices Civilsde Lyon -F

2 Sepsis Incidence in the United States (2000) The incidence of sepsis is greater than most other common diseases, including breast cancer, myocardial infarction, multiple sclerosis, lung cancer, colon cancer, and AIDS. 250 Incidence per 100, Sepsis Breast Cancer Acute Myocardial Infarction Multiple Sclerosis Lung Cancer Colon Cancer AIDS Martin GS, ManninoDM, Eaton S et al. N EnglJ Med. 2003;348: SEER Cancer Statistics Review. National Cancer Institute HIV/AIDS Surveillance Report. Centers for Disease Control. 2001;11. Incidence & Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. NHLBI, NIH TurabelidzeG. J NeurolSci. 2008;269:

3 Septic syndromes and nosocomial infections still a serious a public health concern -Septic syndromes : leading cause of death in ICU - Constant rise for many years (still increasing) -Almost one million cases / year (US) 20 to 30 millions globally -High Mortality (up to 40 % in septic shock) => kill patients every single day (globally)

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5 Sepsis-induced immunosuppression is a profound mechanism Boomer et al. Decreased proinflammatory cytokine production Massive cell loss Lymphoid organs are also affected(post-mortem biopsy) : spleen, lungs(+ circulating blood)

6 Main mechanisms of sepsis-induced immunosuppression immune functions IL-10 (and soluble mediators) Epigenetic regulation Endotoxin tolerance Apoptosis (different mechanisms) Innate Immunity Adaptive Immunity Monocyte/ DC anergy Lymphocyte anergy

7 Consequences of sepsis-induced immunosuppression Accountsfor > 80 % of total mortality

8 Mechanisms of immunesuppression not specific to sepsis Similar anti-inflammatory/ compensatory mechanisms each time SIRS occurs: trauma, surgery, pancreatitis, burns => Applicable to most ICU conditions

9 Monitoring ICU-acquired immunosuppression The objective is to identify the most immunosuppressed patients who could benefit from immunestimulation in order to decrease nosocomial infections / mortality => The best toolsare basedon flow cytometry

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11 : + 86 % : + 11 % Significance: septic patients who died had only a minimal increase in their CD3 T cell counts at day 6 while septic patients who survived almost doubled their CD3 counts.

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13 Gold standard = decreased monocyte HLA-DR

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15 Survival curves stratified on mhla-dr at 30 % at days 3-4 (n = 120 patients) Multivariate analysis : mhla-dr is an independent predictor of mortality (OR = 9) (after adjustment for usual clinical confounders : SAPS II, SOFA, comorbidities )

16 - Multivariate analysis (including usual confonding factors): SOFA, SAPSII, Intubation, catheterization - Competitive risks

17 Does low mhla-dr predict unfavorable outcome in other ICU contexts?

18 Recovery slope (> 1.2) AUC : 0.8

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20 Low mhla-dr predicts nosocomial infections after Day 15

21 ROC Curves Analysis for the prediction secondary infections (AUC = 0.9) According to secondary infection (n = 29 non infected n = 24 infected)

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23 Does low mhla-dr predict unfavorable outcome in other clinical contexts?

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26 Analytical requirements Is mhla-dr measurement standardized? Multicenter study with stabilized blood

27 Inter-laboratory study with clinical samples Bland-Altman The standardized protocol provides excellent inter-lab results

28 What to do with immunomonitoring results (mhla-dr, CD4, % Treg)? Hotchkiss, Monneret, Payen (2013) Lancet Infectious Diseases

29 Immunestimulation and individualized therapy

30 - No side effects - Significantly shorter time of ventilation (148 vs 208 h, p=0.04) - shorter length of intra-hospital stay (59 vs 69 days) - shorter length of ICU stay (41 vs 52) - 28-day mortality not different (trial not powered for mortality)

31 Takehome messages -ICU-acquired immunosuppressionis an additional risk factor for mortality / NI - Biomarker-based prediction of this risk in ICU patients is an emerging but promising field (first results ++) - It could permit individualized care (i.e., stratification and therapy only for patients at high risk) - Different strategies of immunostimulation to be assessed (IL-7, GM-CSF, IFNg )