Clinical Phenotyping for Prognosis and Immunotherapy Guidance in Bacterial Sepsis and COVID-19.

OBJECTIVES: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes. DESIGN: Retrospective analysis of data from prospective clinical studies. SETTING: Greek ICUs and Internal Medicine departments. PATIENTS AND INTERVENTIONS: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, ß was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern. CONCLUSIONS: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications.

Clinical Phenotyping for Prognosis and Immunotherapy Guidance in Bacterial Sepsis and COVID-19.

OBJECTIVES: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes. DESIGN: Retrospective analysis of data from prospective clinical studies. SETTING: Greek ICUs and Internal Medicine departments. PATIENTS AND INTERVENTIONS: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality. MEASUREMENTS AND MAIN RESULTS: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, ß was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern. CONCLUSIONS: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications.

Determinants of health-related quality of life of patients with type 2 diabetes and multimorbidity: a cross-sectional study.

PURPOSE: To examine the determinants of health-related quality of life (HRQoL) of patients with type 2 diabetes (PwD) and multimorbidity (MM) (at least one co-occurring condition besides T2D) among sociodemographic, disease-related, and MM variables and the association of MM with therapeutic targets. METHODS: A total of 179 PwD attending primary care (PC) in Greece answered the 15 dimension HRQoL (15D) questionnaire between August 2019 and October 2020. Sociodemographic, disease-related, and MM characteristics were recorded. MM was categorized as concordant or discordant based on whether or not it was related to the pathophysiology of T2D. Independent predictors of the 15D score were examined in stepwise regression models among sociodemographic, disease-related, and MM variables and the association of MM with glycated hemoglobin (A1C) and low-density lipoprotein cholesterol (LDL-C) was assessed. RESULTS: The mean 15D score was 0.85 ± 0.11 and the mean MM count was 4.3 ± 1.8. Significant predictors of a higher 15D score were male gender, married state, higher monthly income, and more physical activity. Significant predictors of a lower 15D score were employment, depression, musculoskeletal disease, coronary artery disease, neuropathy, and MM count, but discordant had a stronger effect than concordant MM. Increasing MM count was not significantly correlated with A1C and was correlated with lower LDL-C. CONCLUSION: Non-medical (physical activity and sociodemographic) rather than disease-related characteristics and discordant more than concordant co-occurring conditions affected HRQoL of multimorbid PwD who did not have worse (A1C) or achieved better (LDL-C) therapeutic targets. A generalist approach to the non-medical needs and overall health conditions of PwD could be promoted in PC within the social determinants of health and MM.

Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Addition of macrolide antibiotics to ß-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a ß-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. METHODS: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of ß-lactam plus ß-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). FINDINGS: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. INTERPRETATION: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to ß-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. FUNDING: Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Macrolides for better resolution of community-acquired pneumonia: A global meta-analysis of clinical outcomes with focus on microbial aetiology.

OBJECTIVES: This meta-analysis examined the effect of macrolides on resolution of community-acquired pneumonia (CAP) and interpretation of clinical benefit according to microbiology; emphasis is given to data under-reported countries (URCs). METHODS: This meta-analysis included 47 publications published between 1994 and 2022. Publications were analysed for 30-d mortality (58 759 patients) and resolution of CAP (6465 patients). A separate meta-analysis was done for the prevalence of respiratory pathogens in URCs. RESULTS: Mortality after 30 d was reduced by the addition of macrolides (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51-0.82). The OR for CAP resolution when macrolides were added to the treatment regimen was 1.23 (95% CI 1.00-1.52). In the CAP resolution analysis, the most prevalent pathogen was Streptococcus pneumoniae (12.68%; 95% CI 9.36-16.95%). Analysis of the pathogen epidemiology from the URCs included 12 publications. The most prevalent pathogens were S. pneumoniae (24.91%) and Klebsiella pneumoniae (12.90%). CONCLUSION: The addition of macrolides to the treatment regimen led to 35% relative decrease of 30-d mortality and to 23% relative increase in resolution of CAP.

Two-dimensional ultrasound results in underestimation of the ovarian follicle size compared to automated three-dimensional imaging in women undergoing IVF.

BACKGROUND: Traditionally, for the assessment of follicle growth during IVF, two-dimensional (2D) transvaginal ultrasound (US) is used. In the past few years three-dimensional (3D) US has also been introduced. OBJECTIVES: To compare follicular sizes between 2 and 3D ultrasound imaging on the final day of controlled ovarian stimulation. METHODS: A prospective observational cohort study including 121 women undergoing controlled ovarian stimulation (COS) between January 2017 and July 2018. All women were assessed by transvaginal 2D and 3D ultrasonography to measure ovarian follicle dimensions on the final day of COS. RESULTS: The mean difference in paired comparisons between the 3D and 2D US measurements in 25 women with monofollicular development was + 1.6 ± 2.5 mm for the x-dimension and + 1.7 ± 2.4 mm for the y-dimension; and in the total number of 1197 paired measurements of follicles the mean difference + 2.1 ± 3.3 mm and + 1.8 ± 3.9 mm for the x- and y-dimension respectively. In all cases the paired t-test showed that differences were statistically significant (p < 0.01). Further it was conjectured that the 2D underestimation results from the inherent difficulty to precisely place the US probe simultaneously on the perpendicular maximal of the x and y follicle diameters, leading to measurement errors that, by theory, are normally distributed. Running Monte-Carlo simulations based on these measurement errors it was found that both the mean difference and standard deviation are of the same magnitude as the ones found in real measurements, thus proving the conjecture. CONCLUSIONS: The utilisation of 3D US results in different measurements of the follicular dimensions, and volumes, when compared to conventional 2D US. The differences in the x- and y-dimensions may affect the outcome of an IVF cycle as they are used to define the day of triggering final oocyte maturation, which is associated with the yield of mature oocytes and the probability of live birth.

Toward personalized immunotherapy in sepsis: The PROVIDE randomized clinical trial.

The state of immune activation may guide targeted immunotherapy in sepsis. In a double-blind, double-dummy randomized clinical study, 240 patients with sepsis due to lung infection, bacteremia, or acute cholangitis were subjected to measurements of serum ferritin and HLA-DR/CD14. Patients with macrophage activation-like syndrome (MALS) or immunoparalysis were randomized to treatment with anakinra or recombinant interferon-gamma or placebo. Twenty-eight-day mortality was the primary endpoint; sepsis immune classification was the secondary endpoint. Using ferritin >4,420 ng/mL and <5,000 HLA-DR receptors/monocytes as biomarkers, patients were classified into MALS (20.0%), immunoparalysis (42.9%), and intermediate (37.1%). Mortality was 79.1%, 66.9%, and 41.6%, respectively. Survival after 7 days with SOFA score decrease was achieved in 42.9% of patients of the immunotherapy arm and 10.0% of the placebo arm (p = 0.042). Three independent immune classification strata are recognized in sepsis. MALS and immunoparalysis are proposed as stratification for personalized adjuvant immunotherapy. Clinicaltrials.gov registration NCT03332225.

Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.

BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO2/FiO2), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO2/FiO2. In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019-related sepsis is still unclear; we aimed to describe this in a systematic review. DATA SOURCES: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). STUDY SELECTION: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019-related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. DATA EXTRACTION: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. DATA SYNTHESIS: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019-related sepsis prevalence was 77.9% (95% CI, 75.9-79.8; I2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3-36.4; I2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9-23.6; I2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3-90.7; I2 = 98%). CONCLUSIONS: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications.

An open label trial of anakinra to prevent respiratory failure in COVID-19.

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19. Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied. Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata. Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance. Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme. Clinical trial number: NCT04357366.

People infected with the SARS-CoV-2 virus, which causes COVID-19, can develop severe respiratory failure and require a ventilator to keep breathing, but this does not happen to every infected individual. Measuring a blood protein called suPAR (soluble urokinase plasminogen activator receptor) may help identify patients at the greatest risk of developing severe respiratory failure and requiring a ventilator. Previous investigations have suggested that measuring suPAR can identify pneumonia patients at highest risk for developing respiratory failure. The protein can be measured by taking a blood sample, and its levels provide a snapshot of how the body's immune system is reacting to infection, and of how it may respond to treatment. Anakinra is a drug that forms part of a class of medications called interleukin antagonists. It is commonly prescribed alone or in combination with other medications to reduce pain and swelling associated with rheumatoid arthritis. Kyriazopoulou et al. investigated whether treating COVID-19 patients who had developed pneumonia with anakinra could prevent the use of a ventilator and lower the risk of death. The findings show that treating COVID-19 patients with an injection of 100 milligrams of anakinra for ten days may be an effective approach because the drug combats inflammation. Kyriazopoulou et al. examined various markers of the immune response and discovered that anakinra was able to improve immune function, protecting a significant number of patients from going on a ventilator. The drug was also found to be safe and cause no significant adverse side effects. Administering anakinra decreased of the risk of progression into severe respiratory failure by 70%, and reduced death rates significantly. These results suggest that it may be beneficial to use suPAR as an early biomarker for identifying those individuals at highest risk for severe respiratory failure, and then treat them with anakinra. While the findings are promising, they must be validated in larger studies.

Procalcitonin to Reduce Long-Term Infection-associated Adverse Events in Sepsis. A Randomized Trial.

Rationale: Although early antimicrobial discontinuation guided by procalcitonin (PCT) has shown decreased antibiotic consumption in lower respiratory tract infections, the outcomes in long-term sepsis sequelae remain unclear.Objectives: To investigate if PCT guidance may reduce the incidence of long-term infection-associated adverse events in sepsis.Methods: In this multicenter trial, 266 patients with sepsis (by Sepsis-3 definitions) with lower respiratory tract infections, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard of care. The discontinuation criterion was ≥80% reduction in PCT levels or any PCT ≤0.5 µg/L at Day 5 or later. The primary outcome was the rate of infection-associated adverse events at Day 180, a composite of the incidence of any new infection by Clostridioides difficile or multidrug-resistant organisms, or any death attributed to baseline C. difficile or multidrug-resistant organism infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy, and cost of hospitalization.Measurements and Main Results: The rate of infection-associated adverse events was 7.2% (95% confidence interval [CI], 3.8-13.1%; 9/125) versus 15.3% (95% CI, 10.1-22.4%; 20/131) (hazard ratio, 0.45; 95% CI, 0.20-0.98; P = 0.045); 28-day mortality 15.2% (95% CI, 10-22.5%; 19/125) versus 28.2% (95% CI, 21.2-36.5%; 37/131) (hazard ratio, 0.51; 95% CI, 0.29-0.89; P = 0.02); and median length of antibiotic therapy 5 (range, 5-7) versus 10 (range, 7-15) days (P < 0.001) in the PCT and standard-of-care arms, respectively. The cost of hospitalization was also reduced in the PCT arm.Conclusions: In sepsis, PCT guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.Clinical trial registered with www.clinicaltrials.gov (NCT03333304).

A novel optical biosensor for the early diagnosis of sepsis and severe Covid-19: the PROUD study.

BACKGROUND: The accuracy of a new optical biosensor (OB) point-of-care device for the detection of severe infections is studied. METHODS: The OB emits different wavelengths and outputs information associated with heart rate, pulse oximetry, levels of nitric oxide and kidney function. At the first phase, recordings were done every two hours for three consecutive days after hospital admission in 142 patients at high-risk for sepsis by placing the OB on the forefinger. At the second phase, single recordings were done in 54 patients with symptoms of viral infection; 38 were diagnosed with COVID-19. RESULTS: At the first phase, the cutoff value of positive likelihood of 18 provided 100% specificity and 100% positive predictive value for the diagnosis of sepsis. These were 87.5 and 91.7% respectively at the second phase. OB diagnosed severe COVID-19 with 83.3% sensitivity and 87.5% negative predictive value. CONCLUSIONS: The studied OB seems valuable for the discrimination of infection severity.

De-escalation of antimicrobial therapy in ICU settings with high prevalence of multidrug-resistant bacteria: a multicentre prospective observational cohort study in patients with sepsis or septic shock.

BACKGROUND: De-escalation of empirical antimicrobial therapy, a key component of antibiotic stewardship, is considered difficult in ICUs with high rates of antimicrobial resistance. OBJECTIVES: To assess the feasibility and the impact of antimicrobial de-escalation in ICUs with high rates of antimicrobial resistance. METHODS: Multicentre, prospective, observational study in septic patients with documented infections. Patients in whom de-escalation was applied were compared with patients without de-escalation by the use of a propensity score matching by SOFA score on the day of de-escalation initiation. RESULTS: A total of 262 patients (mean age 62.2 ± 15.1 years) were included. Antibiotic-resistant pathogens comprised 62.9%, classified as MDR (12.5%), extensively drug-resistant (49%) and pandrug-resistant (1.2%). In 97 (37%) patients de-escalation was judged not feasible in view of the antibiotic susceptibility results. Of the remaining 165 patients, judged as patients with de-escalation possibility, de-escalation was applied in 60 (22.9%). These were matched to an equal number of patients without de-escalation. In this subset of 120 patients, de-escalation compared with no de-escalation was associated with lower all-cause 28 day mortality (13.3% versus 36.7%, OR 0.27, 95% CI 0.11-0.66, P = 0.006); ICU and hospital mortality were also lower. De-escalation was associated with a subsequent collateral decrease in the SOFA score. Cox multivariate regression analysis revealed de-escalation as a significant factor for 28 day survival (HR 0.31, 95% CI 0.14-0.70, P = 0.005). CONCLUSIONS: In ICUs with high levels of antimicrobial resistance, feasibility of antimicrobial de-escalation was limited because of the multi-resistant pathogens isolated. However, when de-escalation was feasible and applied, it was associated with lower mortality.

Sinus Bradycardia During Targeted Temperature Management: A Systematic Review and Meta-Analysis.

The beneficial effect of sinus bradycardia during targeted temperature management (TTM) in cardiac arrest patients remains doubtful. We aimed to investigate the impact of sinus bradycardia on survival and neurological outcome. MEDLINE (PubMed), Cochrane, Google Scholar, and ClinicalTrials.gov databases were searched for studies reporting on comatose postcardiac arrest patients presenting sinus bradycardia during TTM. Outcomes were the 180-day survival and final neurologic function assessed by the Cerebral Performance Category scale. The effect size on study outcomes is presented as odds ratio (OR) with 95% confidence interval (CI). Two studies with 681 patients were included. Compared to no-sinus bradycardia group, in patients with sinus bradycardia below 50 bpm, a significant effect of sinus bradycardia on reduction of 180-day mortality was reported (OR = 0.42; 95% CI: 0.29-0.59). No heterogeneity was detected. Sinus bradycardia below 50 bpm during TTM may be protective and should be considered in comatose postcardiac arrest patients.

Survival benefit associated with clarithromycin in severe community-acquired pneumonia: A matched comparator study.

Although analysis of retrospective studies has documented survival benefit from the addition of a macrolide to the treatment regimen for community-acquired pneumonia (CAP), no data are available to determine if there is differential efficacy between members of the macrolide family. In order to investigate this, an analysis was undertaken of data from 1174 patients with CAP who met the new Sepsis-3 definitions and were enrolled prospectively in the data registry of the Hellenic Sepsis Study Group. Four well-matched treatment groups were identified with 130 patients per group: clarithromycin and ß-lactam; azithromycin and ß-lactam; respiratory fluoroquinolone and ß-lactam monotherapy. The primary endpoint was comparison of the effects of clarithromycin with ß-lactam monotherapy on 28-day mortality. The secondary endpoint was resolution of CAP. Mortality rates for the clarithromycin, azithromycin, respiratory fluoroquinolone and ß-lactam groups were 20.8%, 33.8% (P=0.026 vs clarithromycin), 32.3% (P=0.049 vs clarithromycin) and 36.2% (P=0.009 vs clarithromycin), respectively. After stepwise Cox regression analysis among all groups, clarithromycin was the only treatment modality associated with a favourable outcome (hazard ratio 0.61; P=0.021). CAP resolved in 73.1%, 65.9% (P=0.226 vs clarithromycin), 58.5% (P=0.009 vs clarithromycin) and 61.5% (P=0.046 vs clarithromycin) of patients, respectively. It is concluded that the addition of clarithromycin to the treatment regimen of patients with severe CAP leads to better survival rates.

Past history of stage I/II solid tumor malignancy impacts considerably on sepsis mortality: a propensity score matching analysis from the hellenic sepsis study group.

BACKGROUND: Whether past history of solid stage I/II inactive cancer has an impact on 28-day mortality of sepsis remains unclear. We aimed to determine the impact of history of stage I or II solid tumor malignancy in complete remission the last 3 years on sepsis outcome. METHODS: Using the database of the Hellenic Sepsis Study Group from 1553 patients with sepsis admitted in the ICU, 83 patients with sepsis by Sepsis-3 definition with past-history of stage I/II inactive solid malignancy the last 3 years were depicted. A comparator group of 83 patients fully matched for age, severity, type of infection and comorbidities was selected by propensity score matching. RESULTS: Mortality after 28 days was 37.3% in the comparator group and 54.2% in the solid tumor stage I/II group (odds ratio for death 1.98; p: 0.030). Following step-wise forward Cox regression analysis, septic shock (hazard ratio 1.80), acute renal injury (hazard ratio 2.06), history of coronary heart disease (hazard ratio 0.36) and history of stage I/II solid tumor malignancy (hazard ratio 1.79) were the only independent variables associated with 28-day mortality. Serum levels of procalcitonin and of soluble urokinase plasminogen activator receptor were similar between the two groups of comparisons. CONCLUSIONS: Past history of stage I/II solid malignancy is an independent risk factor for unfavorable outcome from sepsis the first 28 days.

The effect of obesity and dietary habits on oxidative stress in Hashimoto's thyroiditis

Objective: Increased oxidative stress has been described in patients with Hashimoto's thyroiditis (HT). The aim of the present study was to investigate whether high oxidative stress is further influenced by obesity and dietary habits in euthyroid women with HT. Methods: Two hundred eighteen consecutive euthyroid women with HT were studied and separated in two groups; 102 with thyroxine replacement and 114 without. For the evaluation of oxidative stress, total lipid peroxide levels in serum (TOS) were measured and recoded as 'high TOS' vs 'medium/low TOS'. The type of food and consumption frequency were recorded. Two binary variables were considered; normal vs low fruit consumption and daily vs sporadic vegetable consumption. Results: 'High TOS' was more frequent in women under thyroxine replacement (31.4% vs 14.7%, OR = 2.7, 95% CI: 1.4­5.2). The prevalence of 'high TOS' was higher among overweight/obese women compared to women with normal BMI (30.4% vs 12.5%, OR = 3.1, 95% CI: 1.5­6.4). Low fruit consumption was associated with increased 'high TOS' prevalence (30.6% vs 12.9%, OR = 3.0, 95% CI: 1.4­6.2). Sporadic vegetable consumption was associated with increased 'high TOS' prevalence compared to daily consumption (29.9% vs 13.5%, OR = 2.7, 95% CI: 1.3­5.7). The examined risk factors were independent and additive in their effect on TOS. At least three risk factors had to be concomitantly present for the likelihood of 'high TOS' to be significantly elevated. Conclusions: Oxidative stress is increased in women with HT under thyroxine replacement. Nevertheless, normal BMI, daily fruit and vegetable consumption, all contribute in maintaining oxidative stress at low levels.

The impact of environmental temperature on the diagnosis of gestational diabetes mellitus.

OBJECTIVE: To investigate a probable impact of seasons on the diagnosis of GDM, as well as the specific effect of the environmental temperature on the diagnosis of this clinical entity. PATIENTS AND METHODS: Two observational studies, one retrospective and one prospective, were conducted in a referral center. Study A included retrospectively 7618 pregnant women who underwent a 3-h 100 g OGTT during the 3rd trimester of gestation. Study B prospectively included 768 pregnant women tested in the 3rd trimester of gestation with a 75 g OGTT. Temperature was recorded every day at 09:00 h. RESULTS: Retrospective Study A: GDM prevalence differed significantly by season: winter = 28.1%, summer = 39.2%, spring = 32.4% and autumn = 32.4% (P < 0.0001). The odds ratio for being diagnosed with GDM was much higher during summer 1.65 (95% CI: 1.43-1.90), with spring and autumn following with 1.23 (95% CI: 1.08-1.39) compared to winter. Glucose levels during OGTT were measured: significantly increased blood glucose values were observed at 60, 120 and 180 min in summer, which remained significant after adjustment for age, gestational age, BMI, weight gain during pregnancy and blood pressure. Prospective Study B: At temperatures above 25°C, the average glucose 60-min and 120-min levels were increased. The relative risk for abnormal glucose values at 60 min, when the environmental temperature increased over 25°C, was 2.2 (1.5-3.3). CONCLUSIONS: GDM prevalence in Greece presents seasonal variation, with higher risk during summer due to post glucose load level variations. These variations could be attributed to differences in environmental temperature.