Management of Sepsis-Induced Immunosuppression

Septic shock is associated in some patients with a profound immunosuppression. We hypothesized that GM-CSF would reduce the occurrence of ICU-acquired infections in immunosuppressed septic patients.

Randomized double-blind trial conducted between 2015 and 2018. Adult patients, admitted to ICU, with severe sepsis or septic shock presenting with sepsis-induced immunosuppression defined by mHLA-DR < 8000 ABC (antibodies bound per cell) at day 3 were included. Patients were randomized to receive GM-CSF 125 μg/m² or placebo for 5 days at a 1:1 ratio. The primary outcome was the difference in the number of patients presenting≥1 ICU-acquired infection at day 28 or ICU discharge.

The study was prematurely stopped because of insufficient recruitment. A total of 98 patients were included, 54 in the intervention group and 44 in the placebo group. The two groups were similar except for a higher body mass index and McCabe score in the intervention group. No significant difference was observed between groups regarding ICU-acquired infection (11% vs 11%, p = 1.000), 28-day mortality (24% vs 27%,p = 0.900), or the number or localization of the ICU infections.

GM-CSF had no effect on the prevention of ICU-acquired infection in sepsis immunosuppression, but any conclusion is limited by the early termination of the study leading to low number of included patients.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and a syndrome shaped by pathogen and host factors evolving over time. During sepsis, the absolute number of lymphocytes decreases. CD4+ and CD8+ T cells, B cells, and NK cells are reduced. Lymphocytes are an essential element of the body's defence against pathogens. Interleukin 7 has strong anti-apoptotic properties and induces the proliferation of CD4+ and CD8+ T lymphocytes. IL-15 prompts the generation of mature NK cells in the bone marrow, plays an important role in the generation, cytotoxicity, and survival of CD8+ T lymphocytes, and is essential for the survival of natural killer T (NKT) and intestinal intraepithelial lymphocytes (IELs). The study highlights the importance of monitoring IL-7 levels in patients with sepsis and septic shock, as low levels of this cytokine were associated with an increased risk of mortality. Physicians should consider using IL-7 levels as a biomarker to identify patients who are at higher risk of mortality and may require more aggressive treatment.

Influenza pandemics are unpredictable recurrent events with global health, economic, and social consequences. The objective of this review is to provide an update on the latest developments in early diagnosis and specific treatment of the disease and its complications, particularly with regard to respiratory organ failure. Despite advances in treatment, the rate of mortality in the intensive care unit remains approximately 30%. Therefore, early identification of potentially severe viral pneumonia is extremely important to optimize treatment in these patients. The pathogenesis of influenza virus infection depends on viral virulence and host response. Thus, in some patients, it is associated with an excessive systemic response mediated by an authentic cytokine storm. This process leads to severe primary pneumonia and acute respiratory distress syndrome. Initial prognostication in the emergency department based on comorbidities, vital signs, and biomarkers (e.g., procalcitonin, ferritin, human leukocyte antigen-DR, mid-regional proadrenomedullin, and lactate) is important. Identification of these biomarkers on admission may facilitate clinical decision-making to determine early admission to the hospital or the intensive care unit. These decisions are reached considering pathophysiological circumstances that are associated with a poor prognosis (e.g., bacterial co-infection, hyperinflammation, immune paralysis, severe endothelial damage, organ dysfunction, and septic shock). Moreover, early implementation is important to increase treatment efficacy. Based on a limited level of evidence, all current guidelines recommend using oseltamivir in this setting. The possibility of drug resistance should also be considered. Alternative options include other antiviral drugs and combination therapies with monoclonal antibodies. Importantly, it is not recommended to use corticosteroids in the initial treatment of these patients. Furthermore, the implementation of supportive measures for respiratory failure is essential. Current recommendations are limited, heterogeneous, and not regularly updated. Early intubation and mechanical ventilation is the basic treatment for patients with severe respiratory failure. Prone ventilation should be promptly performed in patients with acute respiratory distress syndrome, while early tracheostomy should be considered in case of planned prolonged mechanical ventilation. Clinical trials on antiviral treatment and respiratory support measures specifically for these patients, as well as specific recommendations for different at-risk populations, are necessary to improve outcomes.

Immune paralysis induced by sepsis, especially dysfunction of CD4⁺ T cells, leads to an increased risk of infection. In sepsis, abnormal differentiation of T lymphocytes is associated with multiorgan dysfunction syndrome. In T lymphocytes, the Orai1/nuclear factor of activated T Cells (NFAT) pathway is a critical mediator of infection, inflammation, and autoimmunity. In this study, we confirmed immunosuppression of splenic CD4⁺ T cells and abnormal differentiation of T lymphocytes in septic mice. Furthermore, we found that the Orai1/NFAT signaling pathway was inhibited in septic mice; however, the overexpression of Orai1 not only improved immune function of T cells in sepsis but also reduced the mortality and organ damage in septic mice. Moreover, the overexpression of Orai1 could reverse the increases in the numbers of T regulatory and T helper 17 cells in septic mice. These data suggest that the Orai1-mediated NFAT signaling pathway can improve sepsis-induced T-lymphocyte immunosuppression and acute organ dysfunction.

Limited knowledge exists on how early host response impacts outcomes in influenza pneumonia.

This study assessed what was the contribution of host immune response at the emergency department on hospital mortality amongst adults with influenza A H1N1pdm09 pneumonia and whether early stratification by immune host response anticipates the risk of death. This is a secondary analysis from a prospective, observational, multicenter cohort comparing 75 adults requiring intensive care with 38 hospitalized in medical wards. Different immune response biomarkers within 24 h of hospitalization and their association with hospital mortality were assessed.

Fifty-three were discharged alive. Non-survivors were associated (p<0.05) with lower lymphocytes (751 vs. 387), monocytes (450 vs. 220) expression of HLA-DR (1,662 vs. 962) and higher IgM levels (178 vs. 152;p<0.01). Lymphocyte subpopulations amongst non-survivors showed a significantly (p<0.05) lower number of TCD3+ (247.2 vs. 520.8), TCD4+ (150.3 vs. 323.6), TCD8+ (95.3 vs. 151.4) and NKCD56+ (21.9 vs. 91.4). Number of lymphocytes, monocytes and NKCD56+ predicted hospital mortality (AUC 0.854). Hospital mortality was independently associated with low HLA-DR values, low number of NKCD56+ cells, and high IgM levels, in a Cox-proportional hazard analysis. A second model, documented that hospital mortality was independently associated with a phenotype combining immunoparalysis with hyperinflammation (HR 5.53; 95%CI 2.16–14.14), after adjusting by predicted mortality.

We conclude that amongst influenza pneumonia, presence of immunoparalysis was a major mortality driver. Influenza heterogeneity was partly explained by early specific host response dysregulations which should be considered to design personalized approaches of adjunctive therapy.

The nature of sepsis is highly complex, and the disease course can differ markedly between patients. In sepsis, the normal inflammatory equilibrium is disturbed, as a result from a systemic proinflammatory and procoagulant response to infection and is associated with a failure to return to the normal homeostasis. Organ dysfunction in patients with sepsis carries an important morbidity and mortality. Although most organs have discrete anatomical boundaries and carry out unified functions, the hematologic system is poorly circumscribed and serves several unrelated functions. As an essential organ for hemostasis, the involvement of the hematological system affects the patient's well-being and requires support in managing sepsis. The hematologic alterations are present in almost every patient with severe sepsis. Among other changes, we commonly see leukocytosis, anemia, thrombocytopenia, and coagulation cascades activation.

One of the critical aspects in managing coagulopathies in the intensive care units is to avoid the correction of laboratory abnormalities unless is a clinical correlation. The hematology system should not be overlooked when assessing a patient with severe sepsis; a thorough clinical evaluation and panel of laboratory tests related to this organ system should be as much part of the work-up as taking the patient's blood pressure and renal monitoring function or measuring liver enzymes. It is key to improving outcomes in patients with this deadly disease.