Plasma Markers of Neutrophil Extracellular Trap Are Linked to Survival but Not to Pulmonary Embolism in COVID-19-Related ARDS Patients.

Introduction: Coronavirus disease 2019 (COVID-19) can cause life-threatening acute respiratory distress syndrome (ARDS). Recent data suggest a role for neutrophil extracellular traps (NETs) in COVID-19-related lung damage partly due to microthrombus formation. Besides, pulmonary embolism (PE) is frequent in severe COVID-19 patients, suggesting that immunothrombosis could also be responsible for increased PE occurrence in these patients. Here, we evaluate whether plasma levels of NET markers measured shorty after admission of hospitalized COVID-19 patients are associated with clinical outcomes in terms of clinical worsening, survival, and PE occurrence. Patients and Methods: Ninety-six hospitalized COVID-19 patients were included, 50 with ARDS (severe disease) and 46 with moderate disease. We collected plasma early after admission and measured 3 NET markers: total DNA, myeloperoxidase (MPO)-DNA complexes, and citrullinated histone H3. Comparisons between survivors and non-survivors and patients developing PE and those not developing PE were assessed by Mann-Whitney test. Results: Analysis in the whole population of hospitalized COVID-19 patients revealed increased circulating biomarkers of NETs in patients who will die from COVID-19 and in patients who will subsequently develop PE. Restriction of our analysis in the most severe patients, i.e., the ones who enter the hospital for COVID-19-related ARDS, confirmed the link between NET biomarker levels and survival but not PE occurrence. Conclusion: Our results strongly reinforce the hypothesis that NETosis is an attractive therapeutic target to prevent COVID-19 progression but that it does not seem to be linked to PE occurrence in patients hospitalized with COVID-19.

Prediction of reactivity during tracheal intubation by pre-laryngoscopy tetanus-induced ANI variation.

The ANI is a nociception monitor based on the high frequency parts of heart rate variability. Tracheal intubation may induce potentially deleterious hemodynamic disturbances or motor reactions if analgesia is inadequate. We investigated whether ANI modification generated by a standardized moderate short tetanic stimulation performed before laryngoscopy could predict hemodynamic or somatic reactions to subsequent intubation. We designed a prospective, interventional, monocentric, pilot study. Regional ethics board approved the study, written informed consent was obtained from each participant. Before laryngoscopy, under steady-state total intravenous anaesthesia with propofol and remifentanil, the ulnar nerve was stimulated with a 5 s tetanus (70 mA, 50 Hz). After another steady-state period, orotracheal intubation was performed. ANI variation, hemodynamic parameters and somatic reactions associated with tetanus and intubation were collected. To assess the predictability of hemodynamic or somatic reaction during laryngoscopy by tetanus-induced ANI variation, we calculated the area under the corresponding Receiver Operating Characteristic curve (AUCROC) and the 95% confidence intervals. Thirty-five patients were analyzed. ANI decreased by 21 ± 17 after tetanus. Regarding the ability of tetanus-induced ANI variation to predict hemodynamic or somatic reactions during subsequent intubation, the AUCROCs [95% CI] were 0.61 [0.41-0.81] and 0.52 [0.31-0.72] respectively. ANI varied after a short moderate tetanic stimulation performed before laryngoscopy but this variation was not predictive of a hemodynamic or somatic reaction during intubation.Trial registration NCT04354311, April 20th 2020, retrospectively registered.

Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients.

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.106) was lower in Provence-Côte d'Azur with a Mediterranean diet (1.9/1.106), and higher in regions with intensive farming or industrialized activities (5 to 20/1.106). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial.

PURPOSE: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years. DESIGN: A national matched case-control study. PARTICIPANTS: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415). METHODS: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression. MAIN OUTCOME MEASURES: Extensive macular atrophy with pseudodrusen status (cases vs. controls). RESULTS: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP. CONCLUSIONS: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.

Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled, multicenter study.

INTRODUCTION: Ventilator-associated tracheobronchitis (VAT) is associated with increased duration of mechanical ventilation. We hypothesized that, in patients with VAT, antibiotic treatment would be associated with reduced duration of mechanical ventilation. METHODS: We conducted a prospective, randomized, controlled, unblinded, multicenter study. Patients were randomly assigned (1:1) to receive or not receive intravenous antibiotics for 8 days. Patients with ventilator-associated pneumonia (VAP) prior to VAT and those with severe immunosuppression were not eligible. The trial was stopped early because a planned interim analysis found a significant difference in intensive care unit (ICU) mortality. RESULTS: Fifty-eight patients were randomly assigned. Patient characteristics were similar in the antibiotic (n = 22) and no antibiotic (n = 36) groups. Pseudomonas aeruginosa was identified in 32% of VAT episodes. Although no difference was found in mechanical ventilation duration and length of ICU stay, mechanical ventilation-free days were significantly higher (median [interquartile range], 12 [8 to 24] versus 2 [0 to 6] days, P < 0.001) in the antibiotic group than in the no antibiotic group. In addition, subsequent VAP (13% versus 47%, P = 0.011, odds ratio [OR] 0.17, 95% confidence interval [CI] 0.04 to 0.70) and ICU mortality (18% versus 47%, P = 0.047, OR 0.24, 95% CI 0.07 to 0.88) rates were significantly lower in the antibiotic group than in the no antibiotic group. Similar results were found after exclusion of patients with do-not-resuscitate orders and those randomly assigned to the no antibiotic group but who received antibiotics for infections other than VAT or subsequent VAP. CONCLUSION: In patients with VAT, antimicrobial treatment is associated with a greater number of days free of mechanical ventilation and lower rates of VAP and ICU mortality. However, antibiotic treatment has no significant impact on total duration of mechanical ventilation. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00122057.

Activation of peroxisome proliferator-activated receptor-alpha by fenofibrate prevents myocardial dysfunction during endotoxemia in rats.

OBJECTIVE: To investigate the effects of fenofibrate, an activator of peroxisome proliferator-activated receptor-alpha, on cardiac function in a rat endotoxemia model. DESIGN: Prospective, randomized, controlled study. SETTING: University research laboratory. SUBJECTS: Three-month-old male Wistar rats. INTERVENTIONS: Animals were fed with standard diet containing no drug or fenofibrate (0.2%) for 14 days. They were then injected intravenously with either 5 mg/kg lipopolysaccharide (LPS and fenofibrate + LPS groups) or saline (control and fenofibrate groups). MEASUREMENTS AND MAIN RESULTS: In the LPS group, body weight loss, metabolic acidosis, and thrombocytopenia confirmed presence of systemic endotoxemia. LPS administration resulted in an early peak in plasma tumor necrosis factor-alpha, decreased cardiac contractility (isolated and perfused heart), reduced myofilament Ca2+ sensitivity (Triton-skinned cardiac fibers), and increased left ventricular nitric oxide (NO) end-oxidation products (NO(x) and NO2), without evidence of myocardial oxidative stress (thiobarbituric acid-reactive substances and antioxidant enzyme activities). Fenofibrate pretreatment (fenofibrate + LPS group) did not alter signs of endotoxemia but prevented reductions in both cardiac contractility and myofilament Ca2+ sensitivity. The peak of plasma tumor necrosis factor-alpha was attenuated, whereas myocardial NO(x) and NO2 remained similar to the LPS group. Oxidative stress was suggested from moderate increase in cardiac thiobarbituric acid-reactive substances and reduced glutathione peroxidase activity. CONCLUSION: Fenofibrate, an activator of peroxisome proliferator-activated receptor-alpha, may prevent endotoxemia-induced cardiac dysfunction and reduction in myofilament Ca2+ sensitivity. Our data also suggest a mediating role for early peak plasma tumor necrosis factor-alpha, but not for myocardial NO production or oxidative stress.

Impact of antifungal treatment on Candida-Pseudomonas interaction: a preliminary retrospective case-control study.

OBJECTIVE: A pathogenic interaction between Candida albicans and Pseudomonas aeruginosa has recently been demonstrated. In addition, experimental and clinical studies identified Candida spp. tracheobronchial colonization as a risk factor for P. aeruginosa pneumonia. The aim of this study was to determine the impact of antifungal treatment on ventilator-associated pneumonia (VAP) or tracheobronchial colonization due to P. aeruginosa. DESIGN AND SETTING: Retrospective observational case-control study conducted in a 30-bed ICU during a 1-year period. PATIENTS AND METHODS: One hundred and two patients intubated and ventilated for longer than 48 h with tracheobronchial colonization by Candida spp. Routine screening for Candida spp. and P. aeruginosa was performed at ICU admission and weekly. Antifungal treatment was based on medical staff decisions. Patients with P. aeruginosa VAP or tracheobronchial colonization were matched (1:2) with patients without P. aeruginosa VAP or tracheobronchial colonization. In case and control patients, risk factors for P. aeruginosa VAP or tracheobronchial colonization were determined using univariate and multivariate analyses. RESULTS: Thirty-six patients (35%) received antifungal treatment. Nineteen patients (18%) developed a P. aeruginosa VAP or tracheobronchial colonization, and all were successfully matched. Antifungal treatment [31% vs 60%; p=0.037, OR (95% CI)=0.67 (0.45-0.90)], and duration of antifungal treatment (7+/-11 vs 14+/-14 days; p=0.045, in case and control patients respectively) were significantly associated with reduced risk for P. aeruginosa VAP or tracheobronchial colonization. Antifungal treatment was the only variable independently associated with P. aeruginosa VAP or tracheobronchial colonization (OR=0.68, 95% CI=0.49-0.90, p=0.046). CONCLUSION: In patients with Candida spp. tracheobronchial colonization, antifungal treatment may be associated with reduced risk for P. aeruginosa VAP or tracheobronchial colonization.

Multiple-drug-resistant bacteria in patients with severe acute exacerbation of chronic obstructive pulmonary disease: Prevalence, risk factors, and outcome.

OBJECTIVE: To determine prevalence, risk factors, and effect on outcome of multiple-drug-resistant (MDR) bacteria in patients with severe acute exacerbation of chronic obstructive pulmonary disease. DESIGN: Prospective, observational, cohort study. SETTING: Thirty-bed medical intensive care unit (ICU) in a university hospital. METHODS: All chronic obstructive pulmonary disease patients with acute exacerbation who required intubation and mechanical ventilation for >48 hrs were eligible during a 4-yr period. Patients with pneumonia or other causes of acute respiratory failure were not eligible. In all patients, quantitative tracheal aspirate was performed at ICU admission (positive at 10 colony-forming units [cfu]/mL). MDR bacteria were defined as methicillin-resistant Staphylococcus aureus, ceftazidime- or imipenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, and extended-spectrum beta-lactamase-producing Gram-negative bacilli. All patients received empirical antibiotic treatment at ICU admission. Univariate and multivariate analyses were used to determine variables associated with MDR bacteria and variables associated with ICU mortality. RESULTS: A total of 857 patients were included, and 304 bacteria were isolated (>/=10 cfu/mL) in 260 patients (30%), including 75 MDR bacteria (24%) in 69 patients (8%). When patients with MDR bacteria were compared with patients without MDR bacteria, previous antimicrobial treatment (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.2-4.7; p = .013) and previous intubation (OR, 31; 95% CI, 12-82; p < .001) were independently associated with MDR bacteria. When patients with bacteria other than MDR or patients with no bacteria were used as a reference group, these risk factors were still independently associated with MDR bacteria. Although ICU mortality rate was higher in patients with MDR bacteria than in patients without MDR bacteria (44% vs. 25%; p = .001; OR, 2.3; 95% CI, 1.4-3.8), MDR bacteria were not independently associated with ICU mortality. Inappropriate initial antibiotic treatment (88% vs. 5%; p = <.001; OR, 6.7; 95% CI, 3.8-12) and ventilator-associated pneumonia (23% vs. 5%; p = <.001; OR, 1.3; 95% CI, 1-1.8) rates were significantly higher in patients with MDR bacteria than in patients with bacteria other than MDR. Inappropriate initial antibiotic treatment was independently associated with increased ICU mortality (OR, 7.1; 95% CI, 1.9-30; p = .003). CONCLUSION: MDR bacteria are common in patients with acute exacerbation of chronic obstructive pulmonary disease requiring intubation and mechanical ventilation. Previous antimicrobial treatment and previous intubation are independent risk factors for MDR bacteria. Although MDR bacteria are not independently associated with ICU mortality, inappropriate initial antibiotic treatment is an independent risk factor for ICU mortality in these patients. Further studies are needed to determine whether broad-spectrum antibiotic treatment is cost-effective in these patients.

Endotoxin-induced myocardial dysfunction in senescent rats.

INTRODUCTION: Aging is associated with a decline in cardiac contractility and altered immune function. The aim of this study was to determine whether aging alters endotoxin-induced myocardial dysfunction. METHODS: Senescent (24 month) and young adult (3 month) male Wistar rats were treated with intravenous lipopolysaccharide (LPS) (0.5 mg/kg (senescent and young rats) or 5 mg/kg (young rats only)), or saline (senescent and young control groups). Twelve hours after injection, cardiac contractility (isolated perfused hearts), myofilament Ca2+ sensitivity (skinned fibers), left ventricular nitric oxide end-oxidation products (NOx and NO2) and markers of oxidative stress (thiobarbituric acid reactive species (TBARS) and antioxidant enzymes) were investigated. RESULTS: LPS (0.5 mg/kg) administration resulted in decreased contractility in senescent rats (left ventricular developed pressure (LVDP), 25 +/- 4 vs 53 +/- 4 mmHg/g heart weight in control; P < 0.05) of amplitude similar to that in young rats with LPS 5 mg/kg (LVDP, 48 +/- 7 vs 100 +/- 7 mmHg/g heart weight in control; P < 0.05). In contrast to young LPS rats (0.5 and 5 mg/kg LPS), myofilament Ca2+ sensitivity was unaltered in senescent LPS hearts. Myocardial NOx and NO2 were increased in a similar fashion by LPS in young (both LPS doses) and senescent rats. TBARS and antioxidant enzyme activities were unaltered by sepsis whatever the age of animals. CONCLUSION: Low dose of LPS induced a severe myocardial dysfunction in senescent rats. Ca2+ myofilament responsiveness, which is typically reduced in myocardium of young adult septic rats, however, was unaltered in senescent rats. If these results are confirmed in in vivo conditions, they may provide a cellular explanation for the divergent reports on ventricular diastolic function in septic shock. In addition, Ca2+-sensitizing agents may not be as effective in aged subjects as in younger subjects.

Impact of ventilator-associated pneumonia on outcome in patients with COPD.

PURPOSES: The aim of this study was to determine the impact of ventilator-associated pneumonia (VAP) on outcome in patients with COPD. METHODS: Prospective, observational, case-control study conducted in a 30-bed ICU during a 5-year period. All COPD patients who required intubation and mechanical ventilation (MV) for > 48 h were eligible. VAP diagnosis was based on clinical, radiographic, and quantitative microbiologic criteria. Patients with unconfirmed VAP were excluded, as well as patients with ventilator-associated tracheobronchitis without subsequent VAP. Matching (1:1) criteria included MV duration before VAP occurrence, age +/- 5 years, simplified acute physiology score II on ICU admission +/- 5, and ICU admission category. Variables associated with ICU mortality were determined using univariate and multivariate analyses. RESULTS: A total of 1,241 patients were eligible; 181 patients (14%) were excluded, including 133 patients for VAT and 48 patients for unconfirmed VAP. VAP developed in 77 patients (6%), and all were successfully matched. Pseudomonas aeruginosa was the most frequently isolated bacteria (31%). ICU mortality rate (64% vs 28%), duration of MV (24 +/- 15 d vs 13 +/- 11 d [+/- SD]), and ICU stay (26 +/- 17 d vs 15 +/- 13 d) were significantly (< 0.001) higher in case patients than in control patients. VAP was the only variable independently associated with ICU mortality (odds ratio [OR], 7.7; 95% confidence interval [CI], 3.2 to 18.6; p < 0.001). In VAP patients who received corticosteroids during their ICU stay compared with those who did not receive corticosteroids, mortality rate (50% vs 82%; OR, 1.8; 95% CI, 1.2 to 2.7; p = 0.002), duration of MV (21 +/- 14 d vs 27 +/- 16 d, p = 0.043), and ICU stay (22 +/- 16 d vs 31 +/- 18 d, p = 0.006) were significantly lower. CONCLUSION: VAP is associated with increased mortality rates and longer duration of MV and ICU stay in COPD patients.