Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, Monneret G, Rimmele T, Blood T, Morre M, Gregoire A, Mayo GA, Blood J, Durum SK, Sherwood ER, Hotchkiss RS


Francois B, Jeannet R, Daix T, Walton AH, Shotwell MS, Unsinger J, Monneret G, Rimmele T, Blood T, Morre M, Gregoire A, Mayo GA, Blood J, Durum SK, Sherwood ER, Hotchkiss RS. This review reports on landmarks of clinical flow cytometry in sepsis and how this single-cell analysis technique permitted to breach the wall of decades of unfruitful anti-inflammatory-based clinical trials in sepsis. strong class=”kwd-title” Keywords: Sepsis, HLA-DR, monocyte, IL-7, PD-1, flow cytometry, Time of Flight mass spectrometry 1.?Sepsis epidemiology and definition On May 2017, the World Health Organization (WHO) recognized sepsis as a global health priority by adopting a resolution to improve the prevention, diagnosis and management of this deadly disease (1). Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection (2). Septic shock is the most severe form L755507 of sepsis in which hypotension persists despite adequate volume resuscitation thus requiring the use of vasopressors. According to recent definitions, in response to an infectious trigger, the unbalanced host (immune) response is at the center of sepsis pathophysiology (2). Sepsis represents a major healthcare problem worldwide. As an example, in the USA sepsis is more frequent than myocardial infarction, breast or colon cancers (3C6). Recent modeling of available data determined the number of cases of sepsis in the entire world to over 20C25 million corresponding to 6 million deaths per annum (7,8). Over years, 28-day mortality has remained high, ranging from 20 % for sepsis to over 40 % for septic shock despite improvement in patients care (fluid resuscitation, source control, antimicrobial therapy). Whereas few therapeutic options evaluated in phase II clinical trials have demonstrated the potential efficacy of immunostimulation in sepsis, to date, no therapeutic intervention targeting host response has specifically been approved and sepsis remains the leading cause of mortality in intensive care units L755507 (ICU)(9,10). In addition, sepsis incidence has dramatically increased over the past decade and is expected to further augment. This rising incidence of documented cases of sepsis has been attributed not only to demographic changes, with a large population of patients with co-morbidities (cancer, diabetes, chronic inflammatory diseases) but also to the expansion of treatments with drugs or invasive medical devices that weaken the immune response. Improved coding of sepsis and its increased awareness has additionally been mentioned as a possible cause (4). More worrisome, the United Nations projects Sema3b that the global human population over the age of 60 will increase by more than threefold in next decades and will exceed the size of the global population of young individuals by 2050. Thus, the burden of sepsis is expected to increase continuously in the forthcoming years as sepsis is a disease of the elderly (incidence increases exponentially with age). Importantly, according to the Centers for Disease Control and Prevention, over $ 22 billion is spent annually on hospitalizations for sepsis in the USA representing the most expensive hospitalization cause in this country (11). Moreover, during hospitalization, septic survivors are at high risk of developing nosocomial infections (due to induced immunosuppression C see below) that are associated not only with an increased morbidity, mortality and hospital length of stay but also with an important augmentation in patients hospitalization costs. Even after hospital / ICU discharge, infections remain the leading cause for patients readmission L755507 and death (12C14). Thus, in all respects, the cumulative burden of L755507 sepsis on public health is dramatically high and sepsis is likely to become the quintessential medical disorder of the 21th century (15). 2.?Novel understanding of sepsis immunology As early as 1975, MacLean, Meakins and colleagues (16C18) reported on the delayed hypersensitivity skin testing in response to recall antigens after injury. This lack of response was associated with enhanced mortality and risk of nosocomial infections which are evocative of immunosuppression. In 1991, the group of Cavaillon observed alterations in inflammatory cytokine response of septic patients blood upon ex vivo LPS challenge suggesting modifications of innate immunity (19). Meanwhile, the group of Richard Hotchkiss made several contributions to the field by reporting on the massive lymphocyte apoptosis in septic mice and patients supporting impairments of adaptive immunity. Simultaneously, the inability of various anti-inflammatory approaches aimed at blocking exuberant inflammation to show any clinical benefit (20) has led clinicians and researchers to reconsider their understanding of immune response in sepsis pathophysiology. From early 2000, it was progressively hypothesized that the host response to sepsis associates a pro-inflammatory phase and an anti-inflammatory compensatory response which could become immunosuppressive (21,22). The main mechanisms sustaining this process have been then progressively discovered and are still regularly reinvestigated at the light of recent technological and scientific.