Consider delayed immunosuppression into the concept of sepsis.

To the Editor: In a position statement, Carlet et al. (1) elegantly discuss the difficulty in using the current concept of sepsis for future clinical trials and propose two new strategies. They conclude that a systematic assessment of potential target mediators should be performed and that the underlying rationale and available data for the intervention should be robust and plausible. The second suggested approach focuses on specific disease-oriented studies. We agree that a dramatic change in study design will be necessary and that the concept of sepsis needs to be reconsidered. Mixing up of patients with various infections in different disease states and immunologic phases in a single clinical trial seems outdated. In addition to the proposed approaches, we suggest a complementary strategy for future clinical trials. This strategy was postulated by us and others a number of years ago (2) and is based on the observation that the vast majority of nonsurviving septic shock patients do not die of the initial burden, but rather from a “second” or “third hit” in later stages of the disease (3). This is due to the fact that most nonsurvivors develop a state of functional immunodeficiency that includes, among others, disturbed monocytic phagocytosis, cytokine profiles, and antigen presentation, as well as dysfunction and apoptosis of lymphocytes, and finally a “shutdown” of innate and adaptive immunity. This state was termed immunoparalysis and may best be approached via standardized quantitative measurement of a diminished monocytic human leukocyte antigen (HLA)-DR expression. Interestingly, although intensivists routinely monitor a wide array of acute organ dysfunctions, the host’s immune system/organ is typically not within the scope and most patients are still characterized using conventional biomarkers such as e.g., highsensitivity C-reactive protein or procalcitonin. These biomarkers, however, do not reflect the respective phase of the host’s response and are inadequate for an assessment of the immunologic dynamics and of cell-mediated immunity (4). In addition to monitoring the clinical course and established biomarkers, we suggest a longitudinal assessment of cell-mediated immunity via standardized HLA-DR measurement (coefficient of variation: intra-lab 3%, interlab 18%). Although more knowledge on the immunopathophysiology of sepsis and more biomarkers for the characterization of cellular immunity is needed, such efforts seem to be a prerequisite for risk stratification, longitudinal follow up, and the design and testing of specific immunologic interventions. Today, the course of monocytic HLA-DR may best reflect the impact of a given immunologic intervention. It can serve as a guide for determining which intervention should be applied at what time to which individual and may assist in both homogenizing study populations and improving the outcome from severe infection. Our proposed strategy thus aims not only to characterize respective patients, but also strives to therapeutically influence the dysregulation which is—at least partially—responsible for the high mortality observed in sepsis (4). Large-scale clinical trials on immunomodulatory therapies that have been demonstrated to reverse this condition may then be performed. Respective approaches include measures of both immunostimulation (e.g., interferonor granulocyte-macrophage colony-stimulating factor [5]) and on selective removal of inhibitory factors (6). We hypothesize that we will not profoundly influence long-term survival from sepsis until we start to focus on the delayed immunosupression and the host response. The authors have not disclosed any potential conflicts of interest.