Early apoptosis of blood monocytes in the septic host: is it a mechanism of protection in the event of septic shock?

Introduction

Based on the central role of the triggering of monocytes for the initiation of the septic cascade, it was investigated whether apoptosis of blood monocytes in septic patients is connected to their final outcome.

Methods

Blood monocytes were isolated from 90 patients with septic syndrome due to ventilator-associated pneumonia on days 1, 3, 5 and 7 from the initiation of symptoms. Apoptosis was defined after incubation with annexin-V-fluorescein isothiocyanate and propidium iodine and reading by a flow cytometer. The function of first-day monocytes was evaluated from the concentrations of tumour necrosis factor alpha (TNFα) and IL-6 in supernatants of cell cultures after triggering with endotoxins. TNFα, IL-6 and IL-8 were estimated in serum by an enzyme immunoassay.

Results

Mortality rates of patients with apoptosis ≤50% compared with patients with apoptosis >50% were 49.12% and 15.15%, respectively (P < 0.0001). Kaplan-Meier analysis showed a 28-day survival benefit in patients with septic shock and monocyte apoptosis >50% compared with those patients with apoptosis ≤50% (P = 0.0032). Production of IL-6 by monocytes on the first day by patients with apoptosis ≤50% was similar compared with monocytes isolated from healthy controls. Serum concentrations of TNFα were higher in patients with monocyte apoptosis ≤50% and septic shock compared with patients with apoptosis >50% on day 7; similar findings occurred for serum IL-6 on days 1 and 7 and for serum IL-8 on days 1 and 5.

Conclusion

Early apoptosis of monocytes upon presentation of clinical signs of sepsis is connected to a favourable outcome. These findings are of particular importance for the patient with septic shock, where they might constitute a mechanism of pathogenesis.

     

Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock

Purpose

We performed a prospective study to evaluate the ability of inflammatory cytokines in discriminating gram-negative from gram-positive bacteremia in septic shock.

Methods

During the study period, the serum inflammatory cytokine levels were measured at the onset of septic shock by flow cytometry in pediatric hematology/oncology patients with septic shock.

Results

One hundred episodes of septic shock were enrolled. Of 97 episodes of monomicrobial infection, 73.2 % were caused by gram-negative bacteremia and 26.8 % by gram-positive bacteremia. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α were closely related to the pediatric index of mortality 2 (PIM2) score and mortality. However, although the PIM2 score and mortality were comparable, the IL-6, IL-10, and TNF-α levels were significantly higher in patients with gram-negative bacteremia (GNB) than those with gram-positive bacteremia (median levels, pg/mL: IL-6: 784.1 vs. 254.4, P = 0.001; IL-10: 192.2 vs. 19.7, P < 0.001; TNF-α: 4.2 vs. 2.0, P < 0.001). Of the three cytokines, IL-10 was the most useful biomarker for GNB prediction in the derivation cohort and a cutoff value of 50 pg/mL showed a sensitivity of 70.8 % and a specificity of 80.0 %, with a positive predictive value of 89.5 %. When this cutoff value was applied to the validation cohort, the sensitivity, specificity, and positive predictive value were 80.9, 75.0, and 90.5 %, respectively.

Conclusions

Flow cytometry-based inflammatory cytokine measurement is a helpful adjuvant approach for early and quick discrimination of gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock which might be useful for evaluating the severity of shock and the selection and/or timely withdrawal or switch of antibiotics.     

Beneficial effects of the heme oxygenase-1/carbon monoxide system in patients with severe sepsis/septic shock

Purpose

We evaluated the relations among the arterial carbon monoxide (CO) concentration, heme oxygenase (HO)-1 expression by monocytes, oxidative stress, plasma levels of cytokines and bilirubin, and the outcome of patients with severe sepsis or septic shock.

Methods

Thirty-six patients who fulfilled the criteria for severe sepsis or septic shock and 21 other patients without sepsis during their stay in the intensive care unit were studied. HO-1 protein expression by monocytes, arterial CO, oxidative stress, bilirubin, and cytokines were measured.

Results

Arterial blood CO, cytokine, and bilirubin levels, and monocyte HO-1 protein expression were higher in patients with severe sepsis/septic shock than in non-septic patients. Increased HO-1 expression was related to the arterial CO concentration and oxidative stress. There was a positive correlation between survival and increased HO-1 protein expression or a higher CO level.

Conclusions

Arterial CO and monocyte HO-1 protein expression were increased in critically ill patients, particularly those with severe sepsis or septic shock, suggesting that oxidative stress is closely related to HO-1 expression. The HO-1/CO system may play an important role in sepsis.     

Time course of endothelial damage in septic shock: prediction of outcome

Introduction

Endothelial damage accounts greatly for the high mortality in septic shock. Higher expression of mediators (IL-6, IL-8, soluble intercellular adhesion molecule 1 [sICAM-1], soluble endothelial-linked adhesion molecule 1 [sELAM-1]) have been described for non-survivors in comparison with survivors. We investigated the predictive value of the mediators IL-6, IL-8, sELAM-1 and sICAM-1 and their time course in intensive care unit patients who developed septic shock with respect to outcome.

Materials and methods

We measured serum levels of IL-6, IL-8, sELAM-1 and sICAM-1 in 40 intensive care unit patients who developed septic shock. Measurements were performed until death or until resolution of septic shock. Clinical and laboratory data were also recorded.

Results

After 48 hours the levels of sELAM-1 and sICAM-1 increased in non-survivors and decreased in survivors. sELAM-1 was predictive for outcome on the third day (P = 0.02) and the fourth day (P = 0.02) after diagnosis of septic shock. This difference in the time course between survivors and non-survivors occurred 7 days before death of the patients (median, 10 days). sICAM-1 levels increased significantly in non-survivors over the study period (P < 0.001). sELAM-1 (P = 0.04), IL-6 (P = 0.04) and IL-8 (P = 0.008) were significantly higher in non-survivors over the whole study period. The age and norepinephrine dose >0.5 μg/kg/min were significantly different between the groups.

Conclusion

sELAM-1 showed a markedly opposing course after 48 hours of septic shock. This adhesion molecule may be a useful early predictor of disease severity in the course of septic shock after early initial treatment of the patients, and might suggest considering endothelial-restoring therapy.     

Clinical aspects and cytokine response in severe H1N1 influenza A virus infection

Introduction

The immune responses in patients with novel A(H1N1) virus infection (nvA(H1N1)) are incompletely characterized. We investigated the profile of Th1 and Th17 mediators and interferon-inducible protein-10 (IP-10) in groups with severe and mild nvA(H1N1) disease and correlated them with clinical aspects.

Methods

Thirty-two patients hospitalized with confirmed nvA(H1N1) infection were enrolled in the study: 21 patients with nvA(H1N1)-acute respiratory distress syndrome (ARDS) and 11 patients with mild disease. One group of 20 patients with bacterial sepsis-ARDS and another group of 15 healthy volunteers were added to compare their cytokine levels with pandemic influenza groups. In the nvA(H1N1)-ARDS group, the serum cytokine samples were obtained on admission and 3 days later. The clinical aspects were recorded prospectively.

Results

In the nvA(H1N1)-ARDS group, obesity and lymphocytopenia were more common and IP-10, interleukin (IL)-12, IL-15, tumor necrosis factor (TNF)α, IL-6, IL-8 and IL-9 were significantly increased versus control. When comparing mild with severe nvA(H1N1) groups, IL-6, IL-8, IL-15 and TNFα were significantly higher in the severe group. In nonsurvivors versus survivors, IL-6 and IL-15 were increased on admission and remained higher 3 days later. A positive correlation of IL-6, IL-8 and IL-15 levels with C-reactive protein and with > 5-day interval between symptom onset and admission, and a negative correlation with the PaO₂:FiO₂ ratio, were found in nvA(H1N1) groups. In obese patients with influenza disease, a significant increased level of IL-8 was found. When comparing viral ARDS with bacterial ARDS, the level of IL-8, IL-17 and TNFα was significantly higher in bacterial ARDS and IL-12 was increased only in viral ARDS.

Conclusions

In our critically ill patients with novel influenza A(H1N1) virus infection, the hallmarks of the severity of disease were IL-6, IL-15, IL-8 and TNFα. These cytokines, except TNFα, had a positive correlation with the admission delay and C-reactive protein, and a negative correlation with the PaO₂:FiO₂ ratio. Obese patients with nvA(H1N1) disease have a significant level of IL-8. There are significant differences in the level of cytokines when comparing viral ARDS with bacterial ARDS.     

Increased MerTK expression in circulating innate immune cells of patients with septic shock

Purpose

A new pathway of three protein tyrosine kinase receptors, namely, the TAM receptor family [Tyro-3, Axl and Mer tyrosine kinase (MerTK)], has recently been described to negatively control immune responses. The objective of this prospective, observational, clinical study was to investigate the expression patterns of TAM receptors in circulating white blood cells collected from patients with septic shock.

Methods

The expression of TAM receptors was measured by flow cytometry in circulating leukocytes from patients with septic shock sampled on days (D) 1–2 (n = 47) and D3–4 (n = 37) after the onset of shock, severe trauma patients at D1–2 after trauma (n = 51) and healthy individuals (n = 23).

Results

On D1–2 after injury, MerTK was overexpressed in monocytes and neutrophils collected from patients with septic shock in comparison with those collected from healthy volunteers and trauma patients. This phenomenon was also observed for mRNA. Conversely, the expression of Tyro-3 and Axl was higher in monocytes from trauma patients versus healthy volunteers or those in septic shock. MerTK expression between D1–2 and D3–4 remained elevated in patients suffering from septic shock who died or developed an intensive care unit-acquired infection, whereas it decreased in patients who recovered uneventfully. This in vivo observed expression pattern was reproduced ex vivo after the incubation of healthy volunteer cells with plasma from septic shock or trauma patients.

Conclusions

MerTK expression in circulating innate immune cells is increased in patients with septic shock in comparison with healthy volunteers and trauma patients. Persistent MerTK overexpression after septic shock is associated with adverse outcome. The role of this family of receptors in the pathophysiology of injury-induced immune dysfunctions deserves to be specifically investigated.     

Neutrophil apoptosis: a marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome

Introduction

Apoptosis of neutrophils (polymorphonuclear neutrophils [PMNs]) may limit inflammatory injury in sepsis and acute respiratory distress syndrome (ARDS), but the relationship between the severity of sepsis and extent of PMN apoptosis and the effect of superimposed ARDS is unknown. The objective of this study was to correlate neutrophil apoptosis with the severity of sepsis and sepsis-induced ARDS.

Methods

A prospective cohort study was conducted in intensive care units of three tertiary hospitals in Porto Alegre, southern Brazil. Fifty-seven patients with sepsis (uncomplicated sepsis, septic shock, and sepsis-induced ARDS) and 64 controls were enrolled. Venous peripheral blood was collected from patients with sepsis within 24 hours of diagnosis. All surgical groups, including controls, had their blood drawn 24 hours after surgery. Control patients on mechanical ventilation had blood collected within 24 hours of initiation of mechanical ventilation. Healthy controls were blood donors. Neutrophils were isolated, and incubated ex vivo, and apoptosis was determined by light microscopy on cytospun preparations. The differences among groups were assessed by analysis of variance with Tukeys.

Results

In medical patients, the mean percentage of neutrophil apoptosis (± standard error of the mean [SEM]) was lower in sepsis-induced ARDS (28% ± 3.3%; n = 9) when compared with uncomplicated sepsis (57% ± 3.2%; n = 8; p < 0.001), mechanical ventilation without infection, sepsis, or ARDS (53% ± 3.0%; n = 11; p < 0.001) and healthy controls (69% ± 1.1%; n = 33; p < 0.001) but did not differ from septic shock (38% ± 3.7%; n = 12; p = 0.13). In surgical patients with sepsis, the percentage of neutrophil apoptosis was lower for all groups when compared with surgical controls (52% ± 3.6%; n = 11; p < 0.001).

Conclusion

In medical patients with sepsis, neutrophil apoptosis is inversely proportional to the severity of sepsis and thus may be a marker of the severity of sepsis in this population.     

Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock

Introduction

Stimulation of beta₂-adrenergic receptors (β₂-ARs) inhibits tumor necrosis factor-alpha (TNF-α) release in monocytes. In septic shock, endogenous catecholamines induce β₂-AR downregulation, leading to an increased TNF-α release. The aims of this study were to analyze the molecular mechanisms of β-adrenergic downregulation and to explore therapeutic interventions with maintained anti-inflammatory efficacy in septic shock using the inhibition of phosphodiesterase 4 (PDE4).

Methods

We conducted in vitro stimulation of peripheral blood mononuclear cells of healthy volunteers (n = 20) and patients with septic shock (n = 20) with lipopolysaccharide (LPS) or Staphylococcus aureus enterotoxin B (SEB) without or with isoprenaline, forskolin (an activator of adenylate cyclase), or ropipram (an inhibitor of PDE4). We also conducted flow cytometric analysis of Toll-like receptor (TLR) 4 and TLR2 surface expression and intracellular TNF-α production of untreated and stimulated CD14⁺ monocytes. Protein expression of β-ARs, of G proteins, of adenylate cyclase, and of TLRs was measured by Western blotting.

Results

Investigations were done by LPS (100 ng/mL) or SEB (10 ng/mL) when TLR4 and TLR2 were maximally expressed. LPS- or SEB-treated CD14⁺ monocytes of healthy volunteers were able to produce TNF-α. This effect was attenuated by isoprenaline, forskolin, or rolipram in a concentration-dependent manner. In CD14⁺ monocytes of patients with septic shock, the anti-inflammatory effect of isoprenaline was completely blunted whereas efficacy of forskolin and rolipram was maintained. CD14⁺ monocytes of healthy volunteers were compared with patients with septic shock: protein expression of β₂-ARs was reduced and inhibitory G protein was increased, whereas no changes in adenylate cyclase and stimulatory G protein were found.

Conclusions

In septic shock, the anti-inflammatory effects of catecholamines are blunted by downregulation of β₂-ARs and upregulation of the inhibitory G protein in CD14⁺ monocytes. Beta-adrenergic downregulation is overcome by inhibitors of PDE4. These results provide a mechanistic rationale for the therapeutic use of selective PDE4 inhibitors in the treatment of septic shock.     

Triggering receptor expressed on myeloid cells-1 expression on monocytes is associated with inflammation but not with infection in acute pancreatitis

Introduction

Acute pancreatitis (AP) is usually a mild and self-limiting disease, but some patients develop a severe form that is associated with high mortality. In AP, local inflammation is followed first by the systemic inflammatory response syndrome and then by the compensatory anti-inflammatory response syndrome, which is defined by low human leukocyte antigen (HLA)-DR expression on monocytes, increased concentration of the anti-inflammatory cytokine IL-10, and decreased monocyte function. Our aim was to measure the expression of triggering receptor expressed on myeloid cells (TREM)-1 (a proposed marker of infection or inflammation) and HLA-DR on monocytes, and the serum concentrations of IL-6 (a proinflammatory cytokine) and IL-10 in patients with AP to determine whether these markers can identify patients at high risk of developing severe AP or infection.

Methods

Fifty healthy volunteers, 18 patients with mild AP, and 11 patients with severe AP were included in this study. Samples were taken at admission and one and three days later. TREM-1 and HLA-DR expression was evaluated by flow cytometry, and soluble TREM-1, IL-6 and IL-10 concentrations were measured by ELISA.

Results

TREM-1 expression was higher in patients with AP than in healthy volunteers, but there was no difference between patients with mild and severe AP. TREM-1 expression was not associated with mortality or with the presence of infection. Soluble TREM-1 concentration in serum was higher in non-survivors than in survivors. HLA-DR expression was lower and IL-6 concentration higher in patients with severe AP and in infected patients.

Conclusions

Increased TREM-1 expression was associated with the presence of inflammation but not infection in AP. In patients with AP, low HLA-DR expression and high IL-6 concentration could predict severity and infection in samples taken shortly after admission.     

Acute respiratory distress syndrome in patients with malignancies

Purpose

Little attention has been given to ARDS in cancer patients, despite their high risk for pulmonary complications. We sought to describe outcomes in cancer patients with ARDS meeting the Berlin definition.

Methods

Data from a cohort of patients admitted to 14 ICUs between 1990 and 2011 were used for a multivariable analysis of risk factors for hospital mortality.

Results

Of 1,004 included patients (86 % with hematological malignancies and 14 % with solid tumors), 444 (44.2 %) had neutropenia. Admission SOFA score was 12 (10–13). Etiological categories were primary infection-related ARDS (n = 662, 65.9 %; 385 bacterial infections, 213 invasive aspergillosis, 64 Pneumocystis pneumonia); extrapulmonary septic shock-related ARDS (n = 225, 22.4 %; 33 % candidemia); noninfectious ARDS (n = 76, 7.6 %); and undetermined cause (n = 41, 4.1 %). Of 387 (38.6 %) patients given noninvasive ventilation (NIV), 276 (71 %) subsequently required endotracheal ventilation. Hospital mortality was 64 % overall. According to the Berlin definition, 252 (25.1 %) patients had mild, 426 (42.4 %) moderate and 326 (32.5 %) severe ARDS; mortality was 59, 63 and 68.5 %, respectively (p = 0.06). Mortality dropped from 89 % in 1990–1995 to 52 % in 2006–2011 (p < 0.0001). Solid tumors, primary ARDS, and later admission period were associated with lower mortality. Risk factors for higher mortality were allogeneic bone-marrow transplantation, modified SOFA, NIV failure, severe ARDS, and invasive fungal infection.

Conclusions

In cancer patients, 90 % of ARDS cases are infection-related, including one-third due to invasive fungal infections. Mortality has decreased over time. NIV failure is associated with increased mortality. The high mortality associated with invasive fungal infections warrants specific studies of early treatment strategies.     

Effect of l-NAME, an inhibitor of nitric oxide synthesis, on plasma levels of IL-6, IL-8, TNFα and nitrite/nitrate in human septic shock

Objectives: We tested the effects of N^G-nitro-L-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, on plasma levels of interleukin (IL) IL-6, IL-8, tumor necrosis factor-alpha (TNFα) and nitrite/nitrate (NO ₂ ^? /NO ₃ ^? ) in patients with severe septic shock. Design: Prospective clinical study. Setting: Surgical intensive care unit at a university hospital. Patients: 11 consecutive patients with severe septic shock. Interventions: Standard hemodynamic measurements were made and blood samples taken at intervals before, during, and after a 12-h infusion of l-NAME 1 mg · kg^?1 ·h^?1 for determination of plasma IL-6, IL-8, TNFα and NO ₂ ^? /NO ₃ ^? concentration. Measurements and results: Patients with sepsis had increased plasma levels of IL-6, IL-8, TNFα, and NO ₂ ^? /NO ₃ ^? (p<0.05). Plasma levels of IL-6, IL-8, and NO ₂ ^? /NO ₃ ^? were negatively correlated with systemic vascular resistance (r=?0.62, r=?0.65, and r=?0.78, respectively, all p<0.05). Continuous infusion of l-NAME increased mean arterial pressure and systemic vascular resistance, with a concomitant reduction in cardiac output (all p<0.01). No significant changes were seen in levels of plasma IL-6, IL-8, and NO ₂ ^? /NO ₃ ^? during the 24-h observation period. Plasma levels of TNFα were significantly reduced during l-NAME infusion compared to baseline (p<0.05). Conclusions: NO plays a role in the cardiovascular derangements of human septic shock. Inhibition of NO synthesis with l-NAME does not promote excessive cytokine release in patients with severe sepsis.     

Steroids in early ARDS?

Citation

Annane D, Sebille V, Bellissant E: Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 2006, 34:22–30 [1].

Background

Experimental evidence suggests that corticosteroids may be beneficial in early acute respiratory distress syndrome (ARDS).

Methods

Objective

To investigate the efficacy of low doses of corticosteroids in septic shock patients with or without early ARDS by post hoc analysis of a previously completed clinical trial.

Design

Retrospective analysis of a placebo-controlled, randomized, double-blind trial of low doses of corticosteroids in septic shock.

Setting

Nineteen intensive care units in France.

Subjects

Among the 300 septic shock patients enrolled, we selected those meeting standard criteria for ARDS at inclusion.

Intervention

Seven-day treatment with 50 mg of hydrocortisone every 6 hrs and 50 μg of 9-alpha-fludrocortisone once a day.

Measurements and main results

There were 177 patients with ARDS (placebo, n = 92; corticosteroids, n = 85) including 129 (placebo, n = 67; corticosteroids, n = 62) nonresponders and 48 (placebo, n = 25; corticosteroids, n = 23) responders. In nonresponders, there were 50 deaths (75%) in the placebo group and 33 deaths (53%) in the steroid group (hazard ratio 0.57, 95% confidence interval 0.36–0.89, p = .013; relative risk 0.71, 95% confidence interval 0.54–0.94, p = .011). The number of days alive and off the ventilator was 2.6 +/- 6.6 in the placebo group and 5.7 +/- 8.6 in the steroid group (p = .006). There was no significant difference between groups in responders. There was no significant difference between groups in the two subsets of patients without ARDS. Adverse events rates were similar in the two groups.

Conclusion

This post hoc analysis shows that a 7-day treatment with low doses of corticosteroids was associated with better outcomes in septic shock-associated early ARDS nonresponders, but not in responders and not in septic shock patients without ARDS.     

Variants at the promoter of the interleukin-6 gene are associated with severity and outcome of pneumococcal community-acquired pneumonia

Purpose

Conflicting results about the role of genetic variability at IL6, particularly the -174 G/C single nucleotide polymorphism (SNP), in sepsis have been reported. We studied the genetic variability at IL6 in patients with community-acquired pneumonia (CAP) and pneumococcal CAP (P-CAP).

Methods

This was a multicenter, prospective observational study. IL6 -174 was analyzed in 1,227 white Spanish patients with CAP (306 with P-CAP). IL6 1753 C/G (N?=?750), 2954 G/C (N?=?845), and haplotypes defined by these SNPs were also studied.

Results

In CAP patients the genotype -174 GG were associated with protection against acute respiratory distress syndrome (ARDS) (p?=?0.008, OR?=?0.4, 95% CI 0.2?C0.8). No other significant associations were observed. However, in patients with P-CAP multivariate analysis adjusted for age, gender, co-morbidity, hospital of origin, and severity (pneumonia severity index, PSI) showed that the IL6 -174 GG genotype was protective against the development of ARDS (p?=?0.002, OR?=?0.25, 95% CI 0.07?C0.79), septic shock (p?=?0.006, OR?=?0.46, 95% CI 0.18?C0.79), and multiple organ dysfunction syndrome (p?=?0.02, OR?=?0.53, 95% CI 0.27?C0.89). P-CAP patients homozygous for IL6 -174 G also showed a higher survival in a logistic regression analysis adjusted for age, gender, co-morbidity, hospital of origin, and PSI (p?=?0.048, OR?=?0.27, 95% CI 0.07?C0.98).

Conclusions

Our results indicate that the IL-6 -174 GG genotype is associated with lower severity and mortality in patients with P-CAP. This effect was higher than that observed in patients with CAP irrespective of the causal pathogen involved. Our results highlight the importance of the causal pathogen in genetic epidemiological studies in sepsis.     

Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?

Introduction

Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic–pituitary–adrenal axis.

Materials and method

This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-α and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death.

Results

On admission, DHEAS was extremely low in septic shock (1.2 ± 0.8 mol/l) in comparison with multiple trauma patients (2.4 ± 0.5 μmol/l; P < 0.05) and control patients (4.2 ± 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 ± 0.3 μmol/l) than did survivors (1.7 ± 1.1 μmol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points.

Conclusion

We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.     

Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research

Purpose

Altered levels of cytokines and chemokines may play a role in cancer- and cancer treatment-related cognitive difficulties. In many neurodegenerative diseases, abnormal concentrations of cytokines and chemokines affect neuronal integrity leading to cognitive impairments, but the role of cytokines in chemotherapy-related cognitive difficulties in cancer patients is not well understood. Patients receiving doxorubicin-based (with cyclophosphamide, or cyclophosphamide plus fluorouracil; AC/CAF) chemotherapy or cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy report experiencing cognitive difficulties; because these regimens work by different modes of action, it is possible that they differentially affect cytokine levels.

Methods

This study examined the relationships between cytokine levels (i.e., IL-6, IL-8, and MCP-1) and type of chemotherapy among 54 early-stage breast cancer patients receiving AC/CAF or CMF. Cytokine levels were assessed at two time-points: prior to on-study chemotherapy cycle?2 (cycle?2) and after two consecutive chemotherapy cycles (prior to on-study cycle?4; cycle?4).

Main results

Analyses of variance using cycle?2 levels as a covariate (ANCOVA) were used to determine differences between chemotherapy groups. Levels of IL-6, IL-8, and MCP-1 increased in the AC/CAF group and decreased in the CMF group; the only significant between-group change was in IL-6 (p?<?0.05).

Conclusions

These results, although preliminary based on the small sample size, suggest that AC/CAF chemotherapy is more cytokine inducing than CMF. Future studies should confirm these results and explore the distinct inflammatory responses elicited by different chemotherapy regimens when assessing cognitive function in cancer patients.     

Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients

Introduction

Septic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients.

Methods

This prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed.

Results

We observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4⁺ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration.

Conclusions

These findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.     

Cytokine markers as predictors of type of respiratory infection in patients during the influenza season

Objective

The objective of this study is to characterize the cytokine response among patients presenting with an influenza-like illness who are infected with the influenza virus, a bacterial pneumonia, or another viral infection. We hypothesize that there are differences in proinflammatory and anti-inflammatory cytokines in relation to cytokines associated with the humoral response during viral and bacterial respiratory infections.

Methods

We enrolled adults who presented to an urban academic emergency department during the 2008 to 2011 influenza seasons with symptoms of fever and a cough. Subjects had nasal aspirates tested by viral culture, and peripheral blood drawn to quantify cytokine concentrations. Cytokine concentrations were compared between groups using the Wilcoxon rank sum test, and receiver operating characteristic curves were calculated.

Results

A total of 80 patients were enrolled: 40 with influenza infection, 14 patients with a bacterial pneumonia as determined by infiltrate on chest x-ray, and 26 patients negative for influenza infection and infiltrate. There were differences between the bacterial pneumonia group, and all other viral infections grouped together with regard to interleukin (IL) 4 (2.66 vs 16.77 pg/mL, P < .001), IL-5 (20.57 vs 57.57 pg/mL, P = .006), IL-6 (403.06 vs 52.69 pg/mL, P < .001), granulocyte macrophage colony-stimulating factor (18.26 vs 66.80 pg/mL, P < .001), and interferon γ (0.0 vs 830.36 pg/mL, P < .001). Interleukin 10 concentrations were elevated in patients with influenza (88.69 pg/mL) compared with all other groups combined (39.19 pg/mL; P = .003).

Conclusion

Cytokines IL-4, IL-5, IL-6, granulocyte macrophage colony-stimulating factor, and interferon γ may serve as distinct markers of bacterial infection in patients with an influenza-like illness, whereas IL-10 is uniquely elevated in influenza patients.     

Elevated plasmatic level of soluble IL-7 receptor is associated with increased mortality in septic shock patients

Purpose

Adjunctive immunoadjuvant therapies are now proposed in the treatment of septic patients that develop immune dysfunctions. However, a prerequisite is to identify patients at high risk of death that would benefit from such therapy. Knowing that rhIL-7 is a putative candidate for septic shock treatment, we evaluated the association between increased plasmatic level of soluble CD127 (sCD127, IL-7 receptor alpha chain) and mortality after septic shock.

Methods

sCD127 plasmatic level was measured in 70 septic shock patients sampled at day 1–2 (D1) and day 3–4 (D3) after the onset of shock and 41 healthy volunteers.

Results

Compared with survivors, non-survivors presented with significantly higher sCD127 concentrations at D1 and D3 (p < 0.001 and p = 0.002). At D1, the area under the receiver operating characteristic curve for sCD127 level association with mortality was 0.846 (p < 0.0001). Kaplan–Meier survival curves illustrated that mortality was significantly different after stratification based on D1 sCD127 level (log rank test, hazard ratio 9.10, p < 0.0001). This association was preserved in multivariate logistic regression analysis including clinical confounders (age, SAPS II and SOFA scores, odds ratio 12.71, p = 0.003). Importantly, patient stratification on both D1 sCD127 value and SAPS II score improved this predictive capacity (log rank test, p = 0.0001).

Conclusions

Increased sCD127 plasmatic level enables the identification of a group of septic shock patients at high risk of death. After confirmation in a larger cohort, this biomarker may be of interest for patient stratification in future clinical trials.     

One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome

Purpose

Advances in supportive care and ventilator management for acute respiratory distress syndrome (ARDS) have resulted in declines in short-term mortality, but risks of death after survival to hospital discharge have not been well described. Our objective was to quantify the difference between short-term and long-term mortality in ARDS and to identify risk factors for death and causes of death at 1 year among hospital survivors.

Methods

This multi-intensive care unit, prospective cohort included patients with ARDS enrolled between January 2006 and February 2010. We determined the clinical characteristics associated with in-hospital and 1-year mortality among hospital survivors and utilized death certificate data to identify causes of death.

Results

Of 646 patients hospitalized with ARDS, mortality at 1 year was substantially higher (41 %, 95 % CI 37–45 %) than in-hospital mortality (24 %, 95 % CI 21–27 %), P < 0.0001. Among 493 patients who survived to hospital discharge, the 110 (22 %) who died in the subsequent year were older (P < 0.001) and more likely to have been discharged to a nursing home, other hospital, or hospice compared to patients alive at 1 year (P < 0.001). Important predictors of death among hospital survivors were comorbidities present at the time of ARDS, and not living at home prior to admission. ARDS-related measures of severity of illness did not emerge as independent predictors of mortality in hospital survivors.

Conclusions

Despite improvements in short-term ARDS outcomes, 1-year mortality is high, mostly because of the large burden of comorbidities, which are prevalent in patients with ARDS.