Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial

Leventogiannis, Konstantinos; Kyriazopoulou, Evdoxia; Antonakos, Nikolaos; Kotsaki, Antigone; Tsangaris, Iraklis; Markopoulou, Dimitra; Grondman, Inge; Rovina, Nikoleta; Théodorou, Vassiliki; Antoniadou, Eleni; Koutsodimitropoulos, Ioannis; Dalekos, George Ν.; Vlachogianni, Glykeria; Akinosoglou, Karolina; Koulouras, V.; Komnos, Apostolos; Kontopoulou, Theano; Prekates, Athanassios; Koutsoukou, Antonia; Meer, J.W.M. van der; Dimοpoulos, George; Kyprianou, Miltiades; Netea, Mihai G.; Giamarellos‐Bourboulis, Evangelos J.

doi:10.1016/j.xcrm.2022.100817

Cited by 44 publications

(52 citation statements)

References 22 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To assess the relationships between adipocytokines and immunological endotypes, the cohort was divided according to immunological endotype (HI [n = 40], UC [n = 55], and IP [n = 62]) based on ferritin concentrations and mHLA-DR expression following the design of the original study (19). The circulating concentrations of the adipocytokines leptin and adiponectin were not significantly different between the immunological endotypes ( P = 0.25 and P = 0.16, respectively; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although the analyzed data in the current study were collected before any trial-related intervention, the preselection resulted in a specific cohort of sepsis patients. The most important distinctive characteristics of the current cohort are the large proportion of patients with pneumonia and the exclusion of patients using immunosuppressive medications (19). Consequently, this preselected population resulted in a more homogeneous population of sepsis patients and reduced potential immune-related confounders.…”

Section: Discussionmentioning

confidence: 99%

“…In this secondary analysis of a prospective study, we used data and biomaterial from a Greek cohort of hospitalized patients with sepsis (19). All patients (18 years or older) with sepsis admitted to 1 of the 14 recruiting study sites in Greece were screened for eligibility.…”

Section: Study Design and Participantsmentioning

confidence: 99%

See 2 more Smart Citations

The Role of Obesity and Plasma Adipocytokines in Immune Dysregulation in Sepsis Patients

Nooijer

Antonakos

Markopoulou

et al. 2022

Shock

Self Cite

View full text Add to dashboard Cite

The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. Methods In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (body mass index [BMI], 18.5-24.9 kg/m 2 ; n = 67), overweight (BMI, 25.0-29.9 kg/m 2 ; n = 56), and obesity (BMI ≥30 kg/m 2 ; n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). Results: Higher circulating concentrations of leptin were observed in patients with obesity compared with patients with normal weight ( P = 0.008) and overweight ( P = 0.02), whereas adiponectin and resistin plasma concentrations were not different ( P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients ( P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted odds ratio, 1.03 per 10 ng/mL; P = 0.04). These associations were not found for leptin and adiponectin. Conclusion: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. Although resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point toward a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Role of Obesity and Plasma Adipocytokines in Immune Dysregulation in Sepsis Patients

Nooijer

Antonakos

Markopoulou

et al. 2022

Shock

Self Cite

View full text Add to dashboard Cite

show abstract

“…The study was performed in 14 clinical sites in Greece between December 2017 and December 2019, in accordance with the applicable rules concerning the review of research ethics committees and informed consent (approval by the National Ethics Committee of Greece 78/17). The primary analysis focused on immunological endotypes [ 7 ]. Patients were classified into immunological endotypes based on serum ferritin concentration and mHLA-DR expression.…”

Section: Methodsmentioning

confidence: 99%

Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background Sepsis is characterized by a dysregulated immune response to infection. The complement system plays an important role in the host defence to pathogens. However, exaggerated complement activation might contribute to a hyperinflammatory state. The interplay between complement activation and inflammation in relationship with adverse outcomes in sepsis patients is unclear. Methods Secondary analysis of complement factors in a prospective study in 209 hospitalized sepsis patients, of whom the majority presented with shock. Concentrations of complement factors C3, C3a, C3c, C5, C5a, and soluble terminal complement complex were assessed in ethylenediaminetetraacetic acid plasma samples collected within 24 h after sepsis diagnosis using enzyme-linked immunosorbent assays. Results The concentration of complement factors in plasma of severely ill sepsis patients indicated profound activation of the complement system (all P < 0.01 compared to healthy controls). Spearman rank correlation tests indicated consistent relationships between the different complement factors measured, but no significant correlations were observed between the complement factors and other inflammatory biomarkers such as leukocyte numbers, C-reactive protein and ferritin concentrations, or HLA-DR expression on monocytes. The concentration of complement factors was not associated with Sequential Organ Failure Assessment score, the incidence of septic shock, and mortality rates (all P > 0.05) in this cohort of patients with high disease severity. Conclusions Once an infection progresses to severe sepsis or septic shock, the complement pathway is already profoundly activated and is no longer related to a dysregulated inflammatory response, nor to clinical outcome. This implies that in this patient category with severe disease, the complement system is activated to such an extent that it no longer has predictive value for clinical outcome.

show abstract

“…This method can effectively identify transcriptomic differences that reflect immunosuppression and low-grade inflammation trajectories between patients with bacterial versus viral sepsis [ 32 , 33 , 34 ], with specific consideration given to the level of expression of cytotoxic genes in those critically ill, severe manifestations and the overexpression of genes [ 35 ] involved during sepsis that cause the efficient clearance of invading pathogens. These patient cohort differences at the single-cell level can guide the use of immunomodulatory therapy [ 36 ], addressing both the scale of severity and the progression of disease by displaying specific functional diversity and the downregulation of effector functions [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing

et al. 2023

View full text Add to dashboard Cite

Critically ill COVID-19 patients start developing single respiratory organ failure that often evolves into multiorgan failure. Understanding the immune mechanisms in severe forms of an infectious disease (either critical COVID-19 or bacterial septic shock) would help to achieve a better understanding of the patient’s clinical trajectories and the success of potential therapies. We hypothesized that a dysregulated immune response manifested by the abnormal activation of innate and adaptive immunity might be present depending on the severity of the clinical presentation in both COVID-19 and bacterial sepsis. We found that critically ill COVID-19 patients demonstrated a different clinical endotype that resulted in an inflammatory dysregulation in mild forms of the disease. Mild cases (COVID-19 and bacterial non severe sepsis) showed significant differences in the expression levels of CD8 naïve T cells, CD4 naïve T cells, and CD4 memory T cells. On the other hand, in the severe forms of infection (critical COVID-19 and bacterial septic shock), patients shared immune patterns with upregulated single-cell transcriptome sequencing at the following levels: B cells, monocyte classical, CD4 and CD8 naïve T cells, and natural killers. In conclusion, we identified significant gene expression differences according to the etiology of the infection (COVID-19 or bacterial sepsis) in the mild forms; however, in the severe forms (critical COVID-19 and bacterial septic shock), patients tended to share some of the same immune profiles related to adaptive and innate immune response. Severe forms of the infections were similar independent of the etiology. Our findings might promote the implementation of co-adjuvant therapies and interventions to avoid the development of severe forms of disease that are associated with high mortality rates worldwide.

show abstract

Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial

Cited by 44 publications

References 22 publications

The Role of Obesity and Plasma Adipocytokines in Immune Dysregulation in Sepsis Patients

The Role of Obesity and Plasma Adipocytokines in Immune Dysregulation in Sepsis Patients

Complement activation in severely ill patients with sepsis: no relationship with inflammation and disease severity

Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing

Contact Info

Product

Resources

About