Immune Functional Testing in Clinics : Feasibility and Prediction of Deleterious Outcomes *

www.ccmjournal. org 367 Nosocomial infections (NIs) remain a serious and frequent complication of (ICUs) hospitalization and represent an important economic burden by significantly increasing hospitalization cost (1). Predicting which patients are at increased risk for developing NI is most likely one of the major challenges in the forthcoming evolution of ICU patients’ care (2). Although plainly obvious, the necessity of a robust immune response to battle against germs has been largely under recognized over years in the assessment of risk factors for NI. Meanwhile, increasing evidences indicate that a delayed immune failure occurs after any systemic inflammatory response syndrome. This is illustrated in ICU patients by infections normally solely pathogenic in an immunocompromised host (3–5). Importantly, this immune suppression has been shown to be induced after a variety of severe injuries leading patients to the ICU: sepsis, trauma, burn, pancreatitis, surgery, and stroke (6). It is thus of major interest to delineate the mechanisms sustaining this immunosuppression in ICU patients. To this purpose, in this issue of Critical Care Medicine (7), Deknuydt et al present an elegant work on the orchestration of immune response in patients with brain injury (BI). These patients present with similar features of immunosuppression and are characterized by high rates of NI (8). Here, the authors investigated BI patient’s immune response within the model of granuloma formation in response to Bacillus Calmette–Guerin. This very interesting model provides in vitro a nice reflection of the coordination of both innate and adaptive immune cells to mount a protective response against a pathogen (9). The most important result of this study is the observation that BI patients developed a significantly lower number of granulomatous structures and that this decrease was even more pronounced in patients who were to develop NI. Another interesting aspect was to show that, in BI patients, granulomatous structures were characterized by poorly differentiated multinucleated cells (indicating a low level of maturity) and by low numbers of natural killers and γδ T cells. These parameters tended to be exemplified in patients with delayed infections. With that said and as duly acknowledged by the authors, the understanding of intimate mechanisms responsible for such results would deserve further investigations (e.g., role of regulatory T cells, decreased monocyte human leukocyte antigen-DR expression). Despite these limitations, this study provides the first observation of a global defect of immune functions in BI patients as illustrated by impaired granuloma formation in response to Bacillus Calmette–Guerin. Beyond these results, the work of Deknuydt et al (7) underlines the interest of functional testing to evaluate the immune response in ICU patients. Indeed, as there is no clinical sign for immune failure, prevention of NI by identification of patients at risk may rely on the use biomarkers. Of them, functional testing remains the gold standard because it directly measures ex vivo the capacity of a cell population to respond to an immune challenge. Here, although the low number of patients precludes any definitive conclusions, these preliminary results tend to indicate that functional testing may be indicative/predictive of deleterious outcomes in clinic. Similarly, two hallmarks of ICU-acquired immunosuppression are usually reported: the decreased monocyte capacity to release proinflammatory cytokines in response to endotoxin challenge and the lowered lymphocyte proliferation. Overall, these protocols provided excellent insights regarding pathophysiology but remain barely usable on a routine clinical monitoring basis (long incubation time, lengthy cell purification procedures, low standardization, etc.). Thus, one major challenge in the forthcoming years is to abolish the gap between comprehensive and compelling studies like that from Deknuydt et al (7) and functional testing usable on routine daily practice. One solution could be the development of surrogate markers of leukocyte functionality. The best example is the decreased expression of the major histocompatibility complex class II molecule human leukocyte antigen-DR on circulating monocytes. This decreased expression has been observed to correlate with monocyte functional response (tumor necrosis factor production after stimulation and antigen presentation capacity) and to be predictive of deleterious outcomes (mortality, nosocomial Immune Functional Testing in Clinics: Feasibility and Prediction of Deleterious Outcomes*