Early Assessment of Leukocyte Alterations at Diagnosis of Septic Shock

Venet, Fabienne; Davin, Fanny; Guignant, Caroline; Larue, Audrey; Cazalis, Marie-Angélique; Darbon, Romain; Allombert, Caroline; Mougin, Bruno; Malcus, Christophe; Poitevin-Later, Françoise; Lepape, Alain; Monneret, Guillaume

doi:10.1097/shk.0b013e3181dc0977

Cited by 168 publications

(145 citation statements)

References 29 publications

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“…The dramatic fall in WBC and lymphocyte numbers in our study (Table 2) is consistent with the study of Muenzer and colleagues, which reported low WBC numbers and immunosuppression in the two-hit mouse model of CLP plus pneumonia (38), and the decreased T-cell number increased apoptosis in septic humans (39). Boomer and colleagues further showed that immunosuppression was present not only in peripheral blood cells but also locally in organs in patients that died of sepsis (40).…”

Section: Discussionsupporting

confidence: 81%

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Griffin

Letson

Dobson

2016

Clin Vaccine Immunol

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Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of a small-volume 0.9% NaCl adenosine, lidocaine, and Mg 2؉ (ALM) bolus and a 4-h intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to that of controls (25%). Four controls died on day 2 to 3, and two died on day 5. Early death was associated with elevated plasma and lung inflammatory markers (interleukin-6 [IL-6], IL-1␤, C-reactive protein), reduced white blood cell (WBC) count, hypoxemia, hypercapnia, acidosis, hyperkalemia, and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil-dominated WBC rebound/overshoot, increased lung oxidant injury, edema, and persistent ischemia. On day 6, seven of eight ALM survivors had inflammatory and immunological profiles not significantly different from those of sham-treated animals. We conclude in the rat model of experimental sepsis that small-volume ALM treatment led to higher survivability at 6 days (88%) than that of controls (25%). Early death in controls (day 2 to 3) was associated with significantly elevated plasma levels of IL-1␤, IL-6, and C-reactive protein, severe plasma lymphocyte deficiency, reduced neutrophils, and acute lung injury. Late death (day 5) was associated with a massive neutrophil inflammatory storm, increased lung injury, and persistent ischemia. Possible mechanisms of ALM protection are discussed. G lobally, 1,000 people die from sepsis every hour, claiming more lives than trauma, heart attack, or cancer (1-3). Sepsis develops from the host's response to an infection involving an overexpression of systemic inflammation, coagulopathy, immune dysfunction, and eventually multiple-organ failure (4,5). Over the past 2 decades, despite new antimicrobial/antifungal agents and advanced life support systems, the case fatality rate for patients with sepsis has remained at 20% to 30% and up to 50% in lowincome countries (3,4,6). An ongoing concern is why do some patients who receive state-of-the-art treatment die and others live? The reasons are complex but appear to be related to the type and unpredictable nature of pathogen progression (2, 5, 7), the degree of autonomic and cardiac dysfunction that develops (8), and the lack of a suitable frontline drug therapy to protect against the inability of the immune system to discriminate self from non-self, causing widespread tissue injury and eventually death.Previously, we have shown in the rat model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP), that smallvolume adenosine, lidocaine, and Mg 2ϩ (ALM) induced a stable, hypotensive state over 5 h with no arrhythmias, significantly less pulmonary edema, and corrected coagulopathy (9). The ALM concept has also translated to the pig model of lipopolysaccharide endotoxemia (10). In comparison to controls, ALM infusion led to a mild hibernation-like state that decreased mean arterial pres...

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Section: Discussionsupporting

confidence: 81%

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Griffin

Letson

Dobson

2016

Clin Vaccine Immunol

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“…Because circulating IL-7 concentration is mostly regulated by its scavenging rate by T cells, such increased concentration is not surprising in markedly lymphopenic hosts such as septic shock patients (Table I) (4,15).…”

Section: Resultsmentioning

confidence: 99%

IL-7 Restores Lymphocyte Functions in Septic Patients

Venet¹,

Foray²,

Villars-Méchin³

et al. 2012

The Journal of Immunology

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172

134

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Septic syndrome is the leading cause of mortality for critically ill patients worldwide. Patients develop lymphocyte dysfunctions associated with increased risk of death and nosocomial infections. In this study, we performed preclinical experiments testing the potential of recombinant human IL-7 (rhIL-7) as a lymphostimulating therapy in sepsis. Circulating IL-7 and soluble IL-7 receptor α-chain (soluble CD127) concentrations were measured in plasma, whereas cellular CD127 expression was evaluated on circulating CD4+ and CD8+ lymphocytes from septic shock patients and healthy volunteers. Lymphocyte proliferation, IFN-γ production, STAT5 phosphorylation, and B cell lymphoma 2 induction were measured ex vivo in response to T cell stimulation in the presence or not of rhIL-7. We show that IL-7 pathway (plasmatic IL-7 concentration and cellular and soluble CD127 expressions) is not overtly altered and remains activable in septic patients. Most importantly ex vivo treatment of patients’ cells with rhIL-7 significantly improves lymphocyte functionality (CD4+ and CD8+ lymphocyte proliferations, IFN-γ production, STAT5 phosphorylation, and B cell lymphoma 2 induction after stimulation). To our knowledge, this constitutes the first report of rhIL-7 ability to restore normal lymphocyte functions in septic patients. These results support the rational for initiating a clinical trial testing rhIL-7 in septic shock.

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“…In humans, sepsis is associated with a severe lymphopenia that also affects circulating NK cells (202). The decreased number of circulating NK cells persists over 1 wk (203).…”

Section: Immune Status Of Nk Cells During Sepsismentioning

confidence: 99%

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

Souza-Fonseca-Guimarães

Adib‐Conquy

Cavaillon

2011

Mol Med

134

125

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Natural killer (NK) cells were first described as immune leukocytes that could kill tumor cells and soon after were reported to kill virus-infected cells. In the mid-1980s, 10 years after their discovery, NK cells were also demonstrated to contribute to the fight against bacterial infection, particularly because of crosstalk with other leukocytes. A wide variety of immune cells are now recognized to interact with NK cells through the production of cytokines such as interleukin (IL)-2, IL-12, IL-15 and IL-18, which boost NK cell activities. The recent demonstration that NK cells express pattern recognition receptors, namely Toll-like and nucleotide oligomerization domain (NOD)-like receptors, led to the understanding that these cells are not only under the control of accessory cells, but can be directly involved in the antibacterial response thanks to their capacity to recognize pathogen-associated molecular patterns. Interferon (IFN)-γ is the predominant cytokine produced by activated NK cells. IFN-γ is a key contributor to antibacterial immune defense. However, in synergy with other inflammatory cytokines, IFN-γ can also lead to deleterious effects similar to those observed during sepsis. Accordingly, as the main source of IFN-γ in the early phase of infection, NK cells display both beneficial and deleterious effects, depending on the circumstances.

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Early Assessment of Leukocyte Alterations at Diagnosis of Septic Shock

Cited by 168 publications

References 29 publications

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

IL-7 Restores Lymphocyte Functions in Septic Patients

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

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Early Assessment of Leukocyte Alterations at Diagnosis of Septic Shock

Cited by 168 publications

References 29 publications

Small-Volume Adenosine, Lidocaine, and Mg 2+ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Small-Volume Adenosine, Lidocaine, and Mg 2+ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

IL-7 Restores Lymphocyte Functions in Septic Patients

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

Contact Info

Product

Resources

About

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics