On the verge of using an immune toolbox in the intensive care unit?
Thanks to earlier recognition of sepsis and advances in its management, most patients with septic shock now survive the early phase of resuscitation, although there remains a high risk of death as a result of a protracted inflammatory response and/or increased susceptibility to secondary complications . Beyond the classical and undisputed endpoint of mortality, intensive care unit (ICU)-acquired infections (IAI) are of real concern . The risk of developing IAI is influenced by multiple clinical factors, including underlying comorbidities, initial severity of sepsis and need for invasive procedures, but these factors do not fully account for the individual risk of IAI.
A number of experimental and clinical studies have indicated that acquired immune suppression largely contributes to the pathophysiology of secondary infections . This concept has emerged at a time when the clinical critical care community has been disappointed with the results of multiple trials of anti-inflammatory sepsis therapies. In addition, while prompt broad-spectrum antimicrobial therapy has been associated with better outcomes at the most severe end of the sepsis spectrum, timely antimicrobial de-escalation, based on microbiologic identification, susceptibility testing and clinical improvement, is an essential strategy to conserve the effectiveness of existing antimicrobials and prevent the emergence of resistance . Clearly, novel approaches to the diagnosis and clinical management of nosocomial infections are urgently needed.
Peronnet and colleagues addressed the performance of alternative molecular biomarkers to predict IAI . Using quantitative real-time PCR, these authors assessed the systemic expression of the prototypic anti-inflammatory cytokine interleukin (IL)-10 and of the CD74 invariant chain involved in the formation and transport of major histocompatibility complex class II proteins and, therefore, a surrogate marker for cell surface HLA-DR expression. They studied 19 healthy volunteers to assess steady-state gene expression and 725 non-immunocompromised patients, including 70% with an infection and 50% with septic shock. The cumulative incidence of IAI was 19%, occurring at a median of 10 days following ICU admission. Sequential whole blood samples were obtained at the time of ICU admission (day 1) and on days 3 and 6. IAI occurred more frequently in patients with a decrease in CD74 mRNA expression between day 1 and day 3 and in patients with higher levels of IL-10 mRNA on day 3. Of note, lymphocyte counts remained similar at all time points in patients with IAI and in those without.
The study has several strengths, including the size of the cohort, which is much larger than usual for this type of investigation, and the statistical analysis, which took into account the competing risks of IAI, such as death and discharge alive from the ICU, and adjusted for some potential confounders at ICU admission, such as sepsis and shock. The time interval between samples and onset of IAI makes it unlikely that the immune dysfunction on day 3 was caused or worsened by the secondary infectious insult, which generally occurred later on. Nonetheless, some limitations have to be highlighted. First, the control subjects were blood donors, and were generally much younger than the patients. The impact of ageing on immune function, the so-called immunosenescence, has rarely been taken into account in such translational studies . Second, CD74 mRNA expression was correlated to HLA-DR measurements by flow cytometry in only a small subset of patients. Most importantly, the study only included a discovery cohort, without a validation cohort.
The major question is how can the results from such exploratory studies be translated to effective clinical application of immunomonitoring for the diagnosis and/or treatment of nosocomial infections? We now have relevant biomarkers to address the immune status of critically ill patients. The collection of RNA is convenient and adapted to the clinical 24/7 ICU setting, although the subsequent steps to gene expression measurements need to be carried out rapidly if they are to be included in a decision-making process. How these molecular tools may actually impact on clinical management remains elusive. Some immune defects are amenable to immune-enhancing therapeutics, and several biomarker-based therapeutic interventions have thus been proposed to prevent or treat IAI, including granulocyte–macrophage colony-stimulating factor and interferon-gamma to reverse monocyte deactivation, IL-7 to stimulate lymphocyte proliferation and anti-checkpoint molecules to restore lymphocyte activation [13, 14, 15]. Furthermore, stratifying the risk of IAI has become essential in modern critical care medicine because the commonly used diagnostic criteria for infection have limited sensitivity and specificity in the ICU and may result in delayed or excessive antibiotic prescription. The study of Peronnet and colleagues  suggests that immune profiling of critically ill patients could be integrated into a multimodal real-time diagnostic work-up of IAI in the near future. This would represent an important step towards more personalized medicine in the ICU.
Compliance with ethical standards
Conflicts of interest
FP, JLV and IML have no competing interests related to the present manuscript.
- 2.van Vught LA, Klein Klouwenberg PM, Spitoni C, Scicluna BP, Wiewel MA, Horn J, Schultz MJ, Nurnberg P, Bonten MJ, Cremer OL, van der Poll T (2016) Incidence, risk factors, and attributable mortality of secondary infections in the intensive care unit after admission for sepsis. JAMA 315:1469–1479CrossRefPubMedGoogle Scholar
- 8.Grimaldi D, Le Bourhis L, Sauneuf B, Dechartres A, Rousseau C, Ouaaz F, Milder M, Louis D, Chiche JD, Mira JP, Lantz O, Pène F (2014) Specific MAIT cell behaviour among innate-like T lymphocytes in critically ill patients with severe infections. Intensive Care Med 40:192–201CrossRefPubMedGoogle Scholar
- 9.Adrie C, Lugosi M, Sonneville R, Souweine B, Ruckly S, Cartier JC, Garrouste-Orgeas M, Schwebel C, Timsit JF (2017) Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission. Ann Intensive Care 7:30CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Shalova IN, Lim JY, Chittezhath M, Zinkernagel AS, Beasley F, Hernandez-Jimenez E, Toledano V, Cubillos-Zapata C, Rapisarda A, Chen J, Duan K, Yang H, Poidinger M, Melillo G, Nizet V, Arnalich F, Lopez-Collazo E, Biswas SK (2015) Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. Immunity 42:484–498CrossRefPubMedGoogle Scholar
- 11.Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AV, Hinds CJ, Knight JC (2016) Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 4:259–271CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Peronnet E, Venet F, Maucort-Boulch D, Friggeri A, Cour M, Argaud L, Allaouchiche B, Floccard B, Aubrun F, Rimmelé T, Thiolliere F, Piriou V, Bohé J, Cazalis M, Barbalat V, Monneret G, Morisset S, Textoris J, Vallin H, Pachot A, Lepape A (2017) Association between mRNA expression of CD74 and IL10 and risk of ICU-acquired infections. A multicenter cohort study. Intensive Care Med. doi:10.1007/s00134-017-4805-1 PubMedPubMedCentralGoogle Scholar
- 13.Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD (2009) Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 180:640–648CrossRefPubMedGoogle Scholar