A genome-wide association study of survival in patients with sepsis

 

by Tamara Hernandez-Beeftink, Beatriz Guillen-Guio, Jose M. Lorenzo-Salazar, Almudena Corrales, Eva Suarez-Pajes, Rui Feng, Luis A. Rubio-Rodríguez, Megan L. Paynton, Raquel Cruz, M. Isabel García-Laorden, Miryam Prieto-González, Aurelio Rodríguez-Pérez, Demetrio Carriedo, Jesús Blanco, Alfonso Ambrós, Elena González-Higueras

 

Critical Care volume 26, Article number: 341 (2022)

 

Background

Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis.

Methods

This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10−8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants.

Findings

We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37–6.78], p = 4.92 × 10−8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury.

Interpretation

We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.

 

Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19

Systemic hypoferremia and severity of hypoxemic respiratory failure in COVID-19

by Akshay Shah, Joe N. Frost, Louise Aaron, Killian Donovan and Hal Drakesmith 

Letter to the Editor: Critical Care volume 24, Article number: 320 (2020) 

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) was declared a pandemic on March 11, 2020 [1]. Risk factors associated with respiratory failure in patients with COVID-19 include older age, neutrophilia and elevated inflammatory and coagulation markers [1]. Inflammation is often accompanied by systemic hypoferremia and low iron levels may impair hypoxia sensing and immunity [2], and increase the risk of thromboembolic complications [3]—which are all of significant concern in COVID-19. However, the iron status of COVID-19 patients is unclear. Therefore, we sought to characterise iron parameters, including serum iron, in COVID-19 intensive care unit (ICU) patients and relate these to disease severity.

Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis

Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis

by Alexandros Rovas, Laura Mareen Seidel, Hans Vink, Timo Pohlkötter, Hermann Pavenstädt, Christian Ertmer, Michael Hessler and Philipp Kümpers

Critical Care: volume 23, Article number: 260 (2019) 

Background:

The endothelial glycocalyx (eGC) covers the luminal surface of the vascular endothelium and plays an important protective role in systemic inflammatory states and particularly in sepsis. Its breakdown leads to capillary leak and organ dysfunction. Moreover, sepsis-induced alterations of sublingual microcirculation are associated with a worse clinical outcome. The present study was performed to investigate the associations between eGC dimensions and established parameters of microcirculation dysfunction in sepsis.

Methods:

This observational, prospective, cross-sectional study included 40 participants, of which 30 critically ill septic patients were recruited from intensive care units of a university hospital and 10 healthy volunteers served as controls. The established microcirculation parameters were obtained sublingually and analyzed according to the current recommendations. In addition, the perfused boundary region (PBR), an inverse parameter of the eGC dimensions, was measured sublingually, using novel data acquisition and analysis software (GlycoCheck™). Moreover, we exposed living endothelial cells to 5% serum from a subgroup of study participants, and the delta eGC breakdown, measured with atomic force microscopy (AFM), was correlated with the paired PBR values.

Results:

In septic patients, sublingual microcirculation was impaired, as indicated by a reduced microvascular flow index (MFI) and a reduced proportion of perfused vessels (PPV) compared to those in healthy controls (MFI, 2.93 vs 2.74, p = 0.002; PPV, 98.53 vs 92.58, p = 0.0004). PBR values were significantly higher in septic patients compared to those in healthy controls, indicating damage of the eGC (2.04 vs 2.34, p < 0.0001). The in vitro AFM data correlated exceptionally well with paired PBR values obtained at the bedside (rs = − 0.94, p = 0.02). Both PBR values and microcirculation parameters correlated well with the markers of critical illness. Interestingly, no association was observed between the PBR values and established microcirculation parameters.

Conclusion:

Our findings suggest that eGC damage can occur independently of microcirculatory impairment as measured by classical consensus parameters. Further studies in critically ill patients are needed to unravel the relationship of glycocalyx damage and microvascular impairment, as well as their prognostic and therapeutic importance in sepsis.

Trial registration:

Retrospectively registered: Clinicaltrials.gov, NCT03960307

Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study

Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study

by Leijte, Guus P.; Kiers, Dorien; van der Heijden, Wouter; Jansen, Aron; Gerretsen, Jelle; Boerrigter, Verin; Netea, Mihai G.; Kox, Matthijs; Pickkers, Peter  

Critical Care Medicine: April 2019 - Volume 47 - Issue 4 - p 508–516

Objective: To investigate immunostimulatory effects of acetylsalicylic acid during experimental human endotoxemia and in sepsis patients.

Design: Double-blind, randomized, placebo-controlled study in healthy volunteers and ex vivo stimulation experiments using monocytes of septic patients.

Setting: Intensive care research unit of an university hospital.

Subjects: Thirty healthy male volunteers and four sepsis patients. Interventions: Healthy volunteers were challenged IV with endotoxin twice, at a 1-week interval, with each challenge consisting of a bolus of 1 ng/kg followed by continuous administration of 1 ng/kg/hr during 3 hours. Volunteers were randomized to acetylsalicylic acid prophylaxis (80 mg acetylsalicylic acid daily for a 14-d period, starting 7 d before the first endotoxin challenge), acetylsalicylic acid treatment (80 mg acetylsalicylic acid daily for the 7-d period in-between both endotoxin challenges), or the control group (receiving placebo). Furthermore, monocytes of sepsis patients were incubated with acetylsalicylic acid preexposed platelets and were subsequently stimulated with endotoxin.

Measurements and Main Results: Acetylsalicylic acid prophylaxis enhanced plasma tumor necrosis factor-α concentrations upon the first endotoxin challenge by 50% compared with the control group (p = 0.02) but did not modulate cytokine responses during the second endotoxin challenge. In contrast, acetylsalicylic acid treatment resulted in enhanced plasma levels of tumor necrosis factor-α (+53%; p = 0.02), interleukin-6 (+91%; p = 0.03), and interleukin-8 (+42%; p = 0.02) upon the second challenge, whereas plasma levels of the key antiinflammatory cytokine interleukin-10 were attenuated (–40%; p = 0.003). This proinflammatory phenotype in the acetylsalicylic acid treatment group was accompanied by a decrease in urinary prostaglandin E metabolite levels (–27% ± 7%; p = 0.01). Ex vivo exposure of platelets to acetylsalicylic acid increased production of tumor necrosis factor-α (+66%) and decreased production of interleukin-10 (–23%) by monocytes of sepsis patients. Conclusions: Treatment, but not prophylaxis, with low-dose acetylsalicylic acid, partially reverses endotoxin tolerance in humans in vivo by shifting response toward a proinflammatory phenotype. This acetylsalicylic acid–induced proinflammatory shift was also observed in septic monocytes, signifying that patients suffering from sepsis-induced immunoparalysis might benefit from initiating acetylsalicylic acid treatment.