Discontinuing ß-lactam treatment after 3 days for patients with community-acquired pneumonia in non-critical care wards (PTC): a double-blind, randomised, placebo-controlled, non-inferiority trial.

BACKGROUND: Shortening the duration of antibiotic therapy for patients admitted to hospital with community-acquired pneumonia should help reduce antibiotic consumption and thus bacterial resistance, adverse events, and related costs. We aimed to assess the need for an additional 5-day course of ß-lactam therapy among patients with community-acquired pneumonia who were stable after 3 days of treatment. METHODS: We did this double-blind, randomised, placebo-controlled, non-inferiority trial (the Pneumonia Short Treatment [PTC]) in 16 centres in France. Adult patients (aged ≥18 years) admitted to hospital with moderately severe community-acquired pneumonia (defined as patients admitted to a non-critical care unit) and who met prespecified clinical stability criteria after 3 days of treatment with ß-lactam therapy were randomly assigned (1:1) to receive ß-lactam therapy (oral amoxicillin 1 g plus clavulanate 125 mg three times a day) or matched placebo for 5 extra days. Randomisation was done using a web-based system with permuted blocks with random sizes and stratified by randomisation site and Pneumonia Severity Index score. Participants, clinicians, and study staff were masked to treatment allocation. The primary outcome was cure 15 days after first antibiotic intake, defined by apyrexia (temperature ≤37·8°C), resolution or improvement of respiratory symptoms, and no additional antibiotic treatment for any cause. A non-inferiority margin of 10 percentage points was chosen. The primary outcome was assessed in all patients who were randomly assigned and received any treatment (intention-to-treat [ITT] population) and in all patients who received their assigned treatment (per-protocol population). Safety was assessed in the ITT population. This study is registered with ClinicalTrials.gov, NCT01963442, and is now complete. FINDINGS: Between Dec 19, 2013, and Feb 1, 2018, 706 patients were assessed for eligibility, and after 3 days of ß-lactam treatment, 310 eligible patients were randomly assigned to receive either placebo (n=157) or ß-lactam treatment (n=153). Seven patients withdrew consent before taking any study drug, five in the placebo group and two in the ß-lactam group. In the ITT population, median age was 73·0 years (IQR 57·0-84·0) and 123 (41%) of 303 participants were female. In the ITT analysis, cure at day 15 occurred in 117 (77%) of 152 participants in the placebo group and 102 (68%) of 151 participants in the ß-lactam group (between-group difference of 9·42%, 95% CI -0·38 to 20·04), indicating non-inferiority. In the per-protocol analysis, 113 (78%) of 145 participants in the placebo treatment group and 100 (68%) of 146 participants in the ß-lactam treatment group were cured at day 15 (difference of 9·44% [95% CI -0·15 to 20·34]), indicating non-inferiority. Incidence of adverse events was similar between the treatment groups (22 [14%] of 152 in the placebo group and 29 [19%] of 151 in the ß-lactam group). The most common adverse events were digestive disorders, reported in 17 (11%) of 152 patients in the placebo group and 28 (19%) of 151 patients in the ß-lactam group. By day 30, three (2%) patients had died in the placebo group (one due to bacteraemia due to Staphylococcus aureus, one due to cardiogenic shock after acute pulmonary oedema, and one due to heart failure associated with acute renal failure) and two (1%) in the ß-lactam group (due to pneumonia recurrence and possible acute pulmonary oedema). INTERPRETATION: Among patients admitted to hospital with community-acquired pneumonia who met clinical stability criteria, discontinuing ß-lactam treatment after 3 days was non-inferior to 8 days of treatment. These findings could allow substantial reduction of antibiotic consumption. FUNDING: French Ministry of Health.

COVID-19 pneumonia: relationship between inflammation assessed by whole-body FDG PET/CT and short-term clinical outcome.

PURPOSE: [18F]-2-Fluoro-2-deoxy-D-glucose PET/CT (FDG PET/CT) is a sensitive and quantitative technic for detecting inflammatory process. Glucose uptake is correlated with an increased anaerobic glycolysis seen in activated inflammatory cells such as monocytes, lymphocytes, and granulocytes. The aim of the study was to assess the inflammatory status at the presumed peak of the inflammatory phase in non-critically ill patients requiring admission for COVID-19. METHODS: Patients admitted with COVID-19 were prospectively enrolled. FDG PET/CT was performed from day 6 to day 14 of the onset of symptoms. Depending on FDG PET/CT findings, patients' profiles were classified as "inflammatory" or "low inflammatory." FDG PET/CT data were compared with chest CT evolution and short-term clinical outcome. All inflammatory sites were reported to screen potential extra-pulmonary tropism. RESULTS: Thirteen patients were included. Maximum standardized uptake values ranged from 4.7 to 16.3 in lungs. All patients demonstrated increased mediastinal lymph nodes glucose uptake. Three patients (23%) presented mild nasopharyngeal, two patients (15%) bone marrow, and five patients (38%) splenic mild increase in glucose uptake. No patient had significant digestive focal or segmental glucose uptake. There was no significant physiological myocardial glucose uptake in all patients except one. There was no correlation between PET lung inflammatory status and chest CT evolution or short-term clinical outcome. CONCLUSION: Inflammatory process at the presumed peak of the inflammatory phase in COVID-19 patients is obvious in FDG PET/CT scans. Glucose uptake is heterogeneous and typically focused on lungs. TRIAL REGISTRATION: NCT04441489. Registered 22 June 2020 (retrospectively registered).

The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

BACKGROUND: There is a lack of validated tools to assess potential disease progression and hospitalisation decisions in patients presenting to the emergency department (ED) with a suspected infection. This study aimed to identify suitable blood biomarkers (MR-proADM, PCT, lactate and CRP) or clinical scores (SIRS, SOFA, qSOFA, NEWS and CRB-65) to fulfil this unmet clinical need. METHODS: An observational derivation patient cohort validated by an independent secondary analysis across nine EDs. Logistic and Cox regression, area under the receiver operating characteristic (AUROC) and Kaplan-Meier curves were used to assess performance. Disease progression was identified using a composite endpoint of 28-day mortality, ICU admission and hospitalisation > 10 days. RESULTS: One thousand one hundred seventy-five derivation and 896 validation patients were analysed with respective 28-day mortality rates of 7.1% and 5.0%, and hospitalisation rates of 77.9% and 76.2%. MR-proADM showed greatest accuracy in predicting 28-day mortality and hospitalisation requirement across both cohorts. Patient subgroups with high MR-proADM concentrations (≥ 1.54 nmol/L) and low biomarker (PCT < 0.25 ng/mL, lactate < 2.0 mmol/L or CRP < 67 mg/L) or clinical score (SOFA < 2 points, qSOFA < 2 points, NEWS < 4 points or CRB-65 < 2 points) values were characterised by a significantly longer length of hospitalisation (p < 0.001), rate of ICU admission (p < 0.001), elevated mortality risk (e.g. SOFA, qSOFA and NEWS HR [95%CI], 45.5 [10.0-207.6], 23.4 [11.1-49.3] and 32.6 [9.4-113.6], respectively) and a greater number of disease progression events (p < 0.001), compared to similar subgroups with low MR-proADM concentrations (< 1.54 nmol/L). Increased out-patient treatment across both cohorts could be facilitated using a derivation-derived MR-proADM cut-off of < 0.87 nmol/L (15.0% and 16.6%), with decreased readmission rates and no mortalities. CONCLUSIONS: In patients presenting to the ED with a suspected infection, the blood biomarker MR-proADM could most accurately identify the likelihood of further disease progression. Incorporation into an early sepsis management protocol may therefore aid rapid decision-making in order to either initiate, escalate or intensify early treatment strategies, or identify patients suitable for safe out-patient treatment.

Correction to: The early identification of disease progression in patients with suspected infection presenting to the emergency department: a multi-centre derivation and validation study.

In the publication of this article [1], there are two errors in contributing author affiliations. This has now been included in this correction article.

Impact of emergency physician experience on decision-making in patients with suspected community-acquired pneumonia and undergoing systematic thoracic CT scan.

OBJECTIVES: To determine whether the impact of a thoracic CT scan on community-acquired pneumonia (CAP) diagnosis and patient management varies according to emergency physician's experience (≤10 vs >10 years). METHODS: Early thoracic CT Scan for Community-Acquired Pneumonia at the Emergency Department is an interventional study conducted from November 2011 to January 2013 in four French emergency departments, and included suspected patients with CAP. We analysed changes in emergency physician CAP diagnosis classification levels before and after CT scan; and their agreement with an adjudication committee. We performed univariate analysis to determine the factors associated with modifying the diagnosis classification level to be consistent with the radiologist's CT scan interpretation. RESULTS: 319 suspected patients with CAP and 136 emergency physicians (75% less experienced with ≤10 years, 25% with >10 years of experience) were included. The percentage of patients whose classification was modified to become consistent with CT scan radiologist's interpretation was higher among less-experienced than experienced emergency physicians (54.2% vs 40.2%; p=0.02). In univariate analysis, less emergency physician experience was the only factor associated with changing a classification to be consistent with the CT scan radiologist's interpretation (OR 1.77, 95% CI 1.01 to 3.10, p=0.04). After CT scan, the agreement between emergency physicians and adjudication committee was moderate for less-experienced emergency physicians and slight for experienced emergency physicians (k=0.457 and k=0.196, respectively). After CT scan, less-experienced emergency physicians modified patient management significantly more than experienced emergency physicians (36.1% vs 21.7%, p=0.01). CONCLUSIONS: In clinical practice, less-experienced emergency physicians were more likely to accurately modify their CAP diagnosis and patient management based on thoracic CT scan than more experienced emergency physicians. TRIAL REGISTRATION NUMBER: NCT01574066.

High heterogeneity in community-acquired pneumonia inclusion criteria: does this impact on the validity of the results of randomized controlled trials?

BACKGROUND: There is no consensus on the most accurate combination of diagnostic criteria to define community acquired pneumonia (CAP). We describe inclusion criteria in randomized controlled trials (RCT) of CAP and assess their performance for the diagnosis of formally identified CAP. METHODS: RCTs related to CAP recorded on ClinicalTrials.gov were analysed. Due to high heterogeneity, we divided close CAP inclusion criteria into patterns (i.e. combinations of inclusion criteria). To assess their diagnostic performances, these CAP definition patterns were applied to a reference population of 319 suspected CAP patients, in whom the CAP diagnosis had been confirmed (n = 163) or excluded (n = 156) by an adjudication committee after a systematic thoracic CT-scan and a 28-day follow-up period. RESULTS: In the 47 RCTs included in the analysis, 42 different CAP inclusion criteria combinations were identified and 8 patterns created. This heterogeneity was not explained either by the trials' methodology or by their objectives. When applied to the reference population, the performance ranges of the 8 definition patterns were 9.8-56.4% for sensitivities, 56.4 97.4% for specificities, 63.6 83.6% for positive predictive values and 50.8-66.7% for negative predictive values. None of the CAP definitions had both sensitivity and specificity superior to 65%. Depending on the CAP definition, the rate of included patients without CAP ("false positives") ranged from 1 to 21%. CONCLUSIONS: CAP diagnostic criteria within RCTs are heterogeneous, which may have far-reaching consequences on validity of RCT results.

Prognostic value of PCT, copeptin, MR-proADM, MR-proANP and CT-proET-1 for severe acute dyspnea in the emergency department: the BIODINER study.

CONTEXT: Acute dyspnea is a frequent complaint in patients attending the emergency department (ED). OBJECTIVE: To evaluate the accuracy of PCT, MR-proANP, MR-proADM, copeptin and CT-proET1 for the risk-stratification of severe acute dyspnea patients presenting to the ED. METHODS: Multicenter prospective study in adult patients with a chief complaint of acute dyspnea. Pro-hormone type biomarkers concentrations were measured on arrival. Combined primary endpoint was a poor outcome. RESULTS: Three hundred and ninety-four patients were included, 137 (35%) met the primary endpoint. MR-proADM was the only biomarker associated with the primary endpoint (odds ratio 1.43 [95%CI: 1.13-1.82], p = 0.003) as were the presence of paradoxical abdominal breathing (odds ratio 2.48 [95%CI: 1.31-4.68]) or cyanosis (odds ratio 3.18 [1.46-6.89]) Conclusions: In patients with severe acute dyspnea in the ED, pro-hormone type biomarkers measurements have a low added value to clinical signs for the prediction of poor outcome.

Prognostic Accuracy of Sepsis-3 Criteria for In-Hospital Mortality Among Patients With Suspected Infection Presenting to the Emergency Department.

Importance: An international task force recently redefined the concept of sepsis. This task force recommended the use of the quick Sequential Organ Failure Assessment (qSOFA) score instead of systemic inflammatory response syndrome (SIRS) criteria to identify patients at high risk of mortality. However, these new criteria have not been prospectively validated in some settings, and their added value in the emergency department remains unknown. Objective: To prospectively validate qSOFA as a mortality predictor and compare the performances of the new sepsis criteria to the previous ones. Design, Settings, and Participants: International prospective cohort study, conducted in France, Spain, Belgium, and Switzerland between May and June 2016. In the 30 participating emergency departments, for a 4-week period, consecutive patients who visited the emergency departments with suspected infection were included. All variables from previous and new definitions of sepsis were collected. Patients were followed up until hospital discharge or death. Exposures: Measurement of qSOFA, SOFA, and SIRS. Main Outcomes and Measures: In-hospital mortality. Results: Of 1088 patients screened, 879 were included in the analysis. Median age was 67 years (interquartile range, 47-81 years), 414 (47%) were women, and 379 (43%) had respiratory tract infection. Overall in-hospital mortality was 8%: 3% for patients with a qSOFA score lower than 2 vs 24% for those with qSOFA score of 2 or higher (absolute difference, 21%; 95% CI, 15%-26%). The qSOFA performed better than both SIRS and severe sepsis in predicting in-hospital mortality, with an area under the receiver operating curve (AUROC) of 0.80 (95% CI, 0.74-0.85) vs 0.65 (95% CI, 0.59-0.70) for both SIRS and severe sepsis (P < .001; incremental AUROC, 0.15; 95% CI, 0.09-0.22). The hazard ratio of qSOFA score for death was 6.2 (95% CI, 3.8-10.3) vs 3.5 (95% CI, 2.2-5.5) for severe sepsis. Conclusions and Relevance: Among patients presenting to the emergency department with suspected infection, the use of qSOFA resulted in greater prognostic accuracy for in-hospital mortality than did either SIRS or severe sepsis. These findings provide support for the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria in the emergency department setting. Trial Registration: clinicaltrials.gov Identifier: NCT02738164.

Early Chest Computed Tomography Scan to Assist Diagnosis and Guide Treatment Decision for Suspected Community-acquired Pneumonia.

RATIONALE: Clinical decision making relative to community-acquired pneumonia (CAP) diagnosis is difficult. Chest radiograph is key in establishing parenchymal lung involvement. However, radiologic performance may lead to misdiagnosis, rendering questionable the use of chest computed tomography (CT) scan in patients with clinically suspected CAP. OBJECTIVES: To assess whether early multidetector chest CT scan affects diagnosis and management of patients visiting the emergency department with suspected CAP. METHODS: A total of 319 prospectively enrolled patients with clinically suspected CAP underwent multidetector chest CT scan within 4 hours. CAP diagnosis probability (definite, probable, possible, or excluded) and therapeutic plans (antibiotic initiation/discontinuation, hospitalization/discharge) were established by emergency physicians before and after CT scan results. The adjudication committee established the final CAP classification on Day 28. MEASUREMENTS AND MAIN RESULTS: Chest radiograph revealed a parenchymal infiltrate in 188 patients. CAP was initially classified as definite in 143 patients (44.8%), probable or possible in 172 (53.8%), and excluded in 4 (1.2%). CT scan revealed a parenchymal infiltrate in 40 (33%) of the patients without infiltrate on chest radiograph and excluded CAP in 56 (29.8%) of the 188 with parenchymal infiltrate on radiograph. CT scan modified classification in 187 (58.6%; 95% confidence interval, 53.2-64.0), leading to 50.8% definite CAP and 28.8% excluded CAP, and 80% of modifications were in accordance with adjudication committee classification. Because of CT scan, antibiotics were initiated in 51 (16%) and discontinued in 29 (9%), and hospitalization was decided in 22 and discharge in 23. CONCLUSIONS: In CAP-suspected patients visiting the emergency unit, early CT scan findings complementary to chest radiograph markedly affect both diagnosis and clinical management. Clinical trial registered with www.clinicaltrials.gov (NCT 01574066).

Routine biological tests in self-poisoning patients: results from an observational prospective multicenter study.

CONTEXT: Routine biological tests are frequently ordered in self-poisoning patients, but their clinical relevance is poorly studied. MATERIALS AND METHODS: This is a prospective multicentric observational study conducted in the emergency departments and intensive care units of 5 university and nonuniversity French hospitals. Adult self-poisoning patients without severely altered vital status on admission were prospectively included. RESULTS: Routine biological test (serum electrolytes and creatinine, liver enzymes, bilirubin, blood cell count, prothrombin time) ordering and results were analyzed. A total of 1027 patients were enrolled (age, 40.2 ± 14 years; women, 61.5%); no patient died during the hospital stay. Benzodiazepine was suspected in more than 70% of cases; 65% (range, 48%-80%) of patients had at least 1 routine biological test performed. At least 1 abnormal test was registered in 23% of these patients. Three factors were associated with abnormal test results: age older than 40 years, male sex, and poisoning with a drug known to alter routine tests (ie, acetaminophen, NSAIDs, metformine, lithium). Depending on these factors, abnormal results ranged from 14% to 48%. Unexpected severe life-threatening conditions were recorded in 6 patients. Only 3 patients were referred to the intensive care unit solely because of abnormal test results. CONCLUSION: Routine biological tests are commonly prescribed in nonsevere self-poisoning patients. Abnormal results are frequent but their relevance at bedside remains limited.

Diagnostic accuracy of C-reactive protein and procalcitonin in suspected community-acquired pneumonia adults visiting emergency department and having a systematic thoracic CT scan.

INTRODUCTION: Community-acquired pneumonia (CAP) requires prompt treatment, but its diagnosis is complex. Improvement of bacterial CAP diagnosis by biomarkers has been evaluated using chest X-ray infiltrate as the CAP gold standard, producing conflicting results. We analyzed the diagnostic accuracy of biomarkers in suspected CAP adults visiting emergency departments for whom CAP diagnosis was established by an adjudication committee which founded its judgment on a systematic multidetector thoracic CT scan. METHODS: In an ancillary study of a multi-center prospective study evaluating the impact of systematic thoracic CT scan on CAP diagnosis, sensitivity and specificity of C-reactive protein (CRP) and procalcitonin (PCT) were evaluated. Systematic nasopharyngeal multiplex respiratory virus PCR was performed at inclusion. An adjudication committee classified CAP diagnostic probability on a 4-level Likert scale, based on all available data. RESULTS: Two hundred patients with suspected CAP were analyzed. The adjudication committee classified 98 patients (49.0 %) as definite CAP, 8 (4.0 %) as probable, 23 (11.5 %) as possible and excluded in 71 (35.5 %, including 29 patients with pulmonary infiltrates on chest X-ray). Among patients with radiological pulmonary infiltrate, 23 % were finally classified as excluded. Viruses were identified by PCR in 29 % of patients classified as definite. Area under the curve was 0.787 [95 % confidence interval (95 % CI), 0.717 to 0.857] for CRP and 0.655 (95 % CI, 0.570 to 0.739) for PCT to detect definite CAP. CRP threshold at 50 mg/L resulted in a positive predictive value of 0.76 and a negative predictive value of 0.75. No PCT cut-off resulted in satisfactory positive or negative predictive values. CRP and PCT accuracy was not improved by exclusion of the 25 (25.5 %) definite viral CAP cases. CONCLUSIONS: For patients with suspected CAP visiting emergency departments, diagnostic accuracy of CRP and PCT are insufficient to confirm the CAP diagnosis established using a gold standard that includes thoracic CT scan. Diagnostic accuracy of these biomarkers is also insufficient to distinguish bacterial CAP from viral CAP. TRIAL REGISTRATION: ClinicalTrials.gov registry NCT01574066 (February 7, 2012).

How emergency physicians use biomarkers: insights from a qualitative assessment of script concordance tests.

OBJECTIVES: Biomarkers have been developed in emergency medicine to improve decision at bedside using Bayesian approach. We intend to determine the cognitive process actually utilised by emergency physicians to incorporate biomarkers in clinical reasoning. DESIGN: We invited eight emergency physicians to answer eight script concordance tests. Interviews were tape-recorded and qualitatively analysed using predetermined categories until saturation. RESULTS: Emergency physicians mainly mobilised intuition and non-Bayesian reasoning to incorporate biomarkers for diagnosis or treatment strategies. CONCLUSIONS: Although biomarkers have been developed to be used in a Bayesian approach, emergency physicians mainly use other analytical and non-analytical cognitive processes to introduce these tools in their clinical reasoning.

Validating the accuracy of deep learning for the diagnosis of pneumonia on chest x-ray against a robust multimodal reference diagnosis: a post hoc analysis of two prospective studies.

BACKGROUND: Artificial intelligence (AI) seems promising in diagnosing pneumonia on chest x-rays (CXR), but deep learning (DL) algorithms have primarily been compared with radiologists, whose diagnosis can be not completely accurate. Therefore, we evaluated the accuracy of DL in diagnosing pneumonia on CXR using a more robust reference diagnosis. METHODS: We trained a DL convolutional neural network model to diagnose pneumonia and evaluated its accuracy in two prospective pneumonia cohorts including 430 patients, for whom the reference diagnosis was determined a posteriori by a multidisciplinary expert panel using multimodal data. The performance of the DL model was compared with that of senior radiologists and emergency physicians reviewing CXRs and that of radiologists reviewing computed tomography (CT) performed concomitantly. RESULTS: Radiologists and DL showed a similar accuracy on CXR for both cohorts (p ≥ 0.269): cohort 1, radiologist 1 75.5% (95% confidence interval 69.1-80.9), radiologist 2 71.0% (64.4-76.8), DL 71.0% (64.4-76.8); cohort 2, radiologist 70.9% (64.7-76.4), DL 72.6% (66.5-78.0). The accuracy of radiologists and DL was significantly higher (p ≤ 0.022) than that of emergency physicians (cohort 1 64.0% [57.1-70.3], cohort 2 63.0% [55.6-69.0]). Accuracy was significantly higher for CT (cohort 1 79.0% [72.8-84.1], cohort 2 89.6% [84.9-92.9]) than for CXR readers including radiologists, clinicians, and DL (all p-values < 0.001). CONCLUSIONS: When compared with a robust reference diagnosis, the performance of AI models to identify pneumonia on CXRs was inferior than previously reported but similar to that of radiologists and better than that of emergency physicians. RELEVANCE STATEMENT: The clinical relevance of AI models for pneumonia diagnosis may have been overestimated. AI models should be benchmarked against robust reference multimodal diagnosis to avoid overestimating its performance. TRIAL REGISTRATION: NCT02467192 , and NCT01574066 . KEY POINT: • We evaluated an openly-access convolutional neural network (CNN) model to diagnose pneumonia on CXRs. • CNN was validated against a strong multimodal reference diagnosis. • In our study, the CNN performance (area under the receiver operating characteristics curve 0.74) was lower than that previously reported when validated against radiologists' diagnosis (0.99 in a recent meta-analysis). • The CNN performance was significantly higher than emergency physicians' (p ≤ 0.022) and comparable to that of board-certified radiologists (p ≥ 0.269).

Exclusive oral antibiotic treatment for hospitalized community-acquired pneumonia: a post-hoc analysis of a randomized clinical trial.

OBJECTIVES: In this study, we aimed to assess the efficacy of different ways of administration and types of beta-lactams for hospitalized community-acquired pneumonia (CAP). METHODS: In this post-hoc analysis of randomized controlled trials (RCT) on patients hospitalized for CAP (pneumonia short treatment trial) comparing 3-day vs. 8-day durations of beta-lactams, which concluded to non-inferiority, we included patients who received either amoxicillin-clavulanate (AMC) or third-generation cephalosporin (3GC) regimens, and exclusively either intravenous or oral treatment for the first 3 days (followed by either 5 days of oral placebo or AMC according to randomization). The choice of route and molecule was left to the physician in charge. The main outcome was a failure at 15 days after the first antibiotic intake, defined as temperature >37.9°C, and/or absence of resolution/improvement of respiratory symptoms, and/or additional antibiotic treatment for any cause. The primary outcome according to the route of administration was evaluated through logistic regression. Inverse probability treatment weighting with a propensity score model was used to adjust for non-randomization of treatment routes and potential confounders. The difference in failure rates was also evaluated among several sub-populations (AMC vs. 3GC treatments, intravenous vs. oral AMC, patients with multi-lobar infection, patients aged ≥65 years old, and patients with CURB65 scores of 3-4). RESULTS: We included 200 patients from the original trial, with 93/200 (46.5%) patients only treated with intravenous treatment and 107/200 (53.5%) patients only treated with oral therapy. The failure rate at Day 15 was not significantly different among patients treated with initial intravenous vs. oral treatment [25/93 (26.9%) vs. 28/107 (26.2%), adjusted odds ratios (aOR) 0.973 (95% CI 0.519-1.823), p 0.932)]. Failure rates at Day 15 were not significantly different among the subgroup populations. DISCUSSION: Among hospitalized patients with CAP, there was no significant difference in efficacy between initial intravenous and exclusive oral treatment. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT01963442.

SEPSIGN: early identification of sepsis signs in emergency department.

Because 20-30% of patients with sepsis deteriorate to critical illness, biomarkers that provide accurate early prognosis may identify which patients need more intensive treatment versus safe early discharge. The objective was to test the performance of sVEGFR2, suPAR and PCT, alone or combined with clinical signs and symptoms, for the prediction of clinical deterioration. This prospective observational study enrolled patients with suspected infection who met SIRS criteria without organ dysfunction (delta SOFA <2 from baseline) from 16 emergency departments. The primary endpoint was clinical deterioration (increased SOFA score ≥2 points, new or increased organ support, or death) within 72 hours of enrollment. Diagnosis and classification of infection status were adjudicated. 724 patients were enrolled, (54% men, median age 55 [38-70] y-o). Infection origin was abdominopelvic (21%), skin and soft tissues (17%), urinary (16%) and pulmonary (15%). 176 (24%) patients deteriorated, with a 28-day mortality of 1.4%. They had lower sVEGFR2 level (6.17 [5.00-7.40] vs 6.52 [5.40-7.84], p=0.024), higher circulating suPAR (5.25 [3.86-7.50] vs 4.18 [3.16-5.68], p<0.001) and higher PCT level (0.32 [0.08-1.80] vs 0.18 [0.05-0.98], p=0.004). suPAR demonstrated superior performance (AUC=0.65 [0.60-0.70]), compared to other biomarkers (PCT, AUC=0.57 [0.52-0.62] and sVEGFR2, AUC=0.58 [0.53-0.64]). Maximum accuracy was achieved from the combination of clinical information, sVEGFR2 and suPAR, yielding an AUC of 0.74 [0.69-0.78] and NPV 0.90 [0.88-0.94]. sVEGFR2 and suPAR were insufficiently accurate to rule out clinical deterioration. Panels of biomarkers will likely be needed to capture the heterogeneous mechanistic pathways involved in sepsis-related organ failure.

Are clinical trials dealing with severe infection fitting routine practices? Insights from a large registry.

INTRODUCTION: Guidelines dealing with severe sepsis and septic shock mostly rely on randomized controlled trials (RCTs) to ensure the best standards of care for patients. However, patients included in high-quality studies may differ from the routine population and alter external validity of recommendations. We aimed to determine to what extent non-inclusion criteria of RCTs dealing with severe sepsis and septic shock may affect application of their conclusions in routine care. METHODS: In a first step, the MEDLINE database was searched for RCTs treating severe sepsis and septic shock patients between 1992 and 2008, and non-inclusion criteria for these studies were abstracted. Two reviewers independently evaluated the articles, which were checked by a third reviewer. We extracted data on the study design, main intervention, primary endpoint, criteria for inclusion, and criteria for non-inclusion. In a second step, the distribution of the non-inclusion criteria was observed in a prospective multicenter cohort of severe sepsis and septic shock patients (Cub-Rea network, 1992 to 2008). RESULTS: We identified 96 articles out of 7,012 citations that met the screening criteria. Congestive heart failure (35%) and cancer (30%) were frequent exclusion criteria in selected studies, as well as other frequent disorders such as gastrointestinal and liver diseases and all causes of immune suppression. Of the 67,717 patients with severe sepsis and septic shock in the Cub-Rea database, 40,325 (60%) experienced at least one of the main exclusion criteria, including 11% of congestive heart failure patients and 11% of cancer patients. In addition, we observed a significant trend for increasing number of patients with these criteria along time. CONCLUSION: Current exclusion criteria for RCTs dealing with severe sepsis and septic shock excluded most patients encountered in daily practice and limit external validity of the results of high-quality studies.

Nurses' understanding influences comprehension of patients admitted in the observation unit.

Comprehension is poor in patients admitted in the emergency observation unit. Teamwork communication gaps could contribute to patients' misunderstanding of their health condition. To determine in patients admitted in the emergency observation unit whether comprehension of diagnosis, prognosis, and management depended on nurses' comprehension, the authors conducted a prospective observational study in a busy adult emergency department of a tertiary teaching hospital in Paris over 2 months. Consecutive patients admitted in the emergency observation unit were included. Patients' and nurses' comprehension of diagnosis, prognosis, and management was compared with the statements of the emergency department attending physicians for these items. The authors observed whether patients' misunderstanding was associated with nurses' misunderstanding. A total of 544 patients were evaluated. For each patient, nurses' and patients' comprehension was available. Patients understood severity in 40%, organ involved in 69%, medical wording in 57%, reason for admission in 48%, and discharge instruction in 67%. In comparison with patients, nurses better understood each item except for discharge instruction. The authors observed that patients' comprehension was better when nurses understood diagnosis (p <.0001), reasons for admission (p =.032) and discharge instructions (p =.002). Nurses' understanding of severity did not modify patients' comprehension. These results support the conclusions that communication gaps in teamwork alter patients' comprehension and that nurses' and patients' misunderstandings are associated. Therefore, improving communication by nurses and physicians to patients may improve patients' understanding.

Effect of diagnosis level of certainty on adherence to antibiotics' guidelines in ED patients with pneumonia: a post-hoc analysis of an interventional trial.

BACKGROUND AND IMPORTANCE: Clinical diagnosis of community-acquired pneumonia (CAP) is difficult to establish with certainty. Adherence to antibiotic guidelines independently affects the prognosis of CAP patients. OBJECTIVE: We aimed to determine whether guidelines' adherence was related to CAP diagnosis level of certainty and could be reinforced accordingly to diagnosis improvement. DESIGN: Secondary analysis of a prospective, multicenter study, which evaluated the impact of early thoracic CT scan on diagnosis and therapeutic plan in patients with clinically suspected CAP visiting emergency departments. SETTING AND PARTICIPANTS: In total 319 patients with clinically suspected CAP were enrolled in four emergency departments, Paris, France, between Nov 2011 and Jan 2013. OUTCOME MEASURES AND ANALYSIS: We evaluated guidelines' adherence before and after CT scan and its relationship with CAP diagnosis level of certainty. Antibiotics were categorized as adherent according to 2010 French guidelines. CAP diagnosis level of certainty was prospectively classified by the emergency physicians based on a Likert scale as excluded, possible, probable or definite before and immediately after the CT scan. These classifications and therapeutic plans were also completed by an independent adjudication committee. Determinants of adherence were assessed using Poisson regression with robust variance. MAIN RESULTS: Adherence to guidelines increased from 34.2% before CT scan to 51.3% after CT scan [difference 17.1% (95% CI, 9.5-24.7)], meanwhile CAP diagnosis with high level of certainty (definite and excluded CAP) increased from 46.1 to 79.6% [difference 33.5% (95% CI, 26.5-40.5)]. Diagnosis level of certainty before CT scan was the strongest determinant of adherence in multivariate analysis (RR, 2.63; 95% CI, 1.89-3.67). CONCLUSION: Antibiotic guidelines' adherence was poor and positively related to CAP diagnosis level of certainty. The results suggest that improvements in CAP diagnosis may increase adherence to antibiotic guidelines. Clinical trial registered with www.clinicaltrials.gov (NCT01574066).

Management of patients suffering from mild traumatic brain injury 2023.

OBJECTIVE: To develop a multidisciplinary French reference that addresses initial pre- and in-hospital management of a mild traumatic brain injury patient. DESIGN: A panel of 22 experts was formed on request from the French Society of Emergency Medicine (SFMU) and the French Society of Anaesthesiology and Critical Care Medicine (SFAR). A policy of declaration and monitoring of links of interest was applied and respected throughout the process of producing the guidelines. Similarly, no funding was received from any company marketing a health product (drug or medical device). The expert panel had to respect and follow the Grade® (Grading of Recommendations Assessment, Development and Evaluation) methodology to evaluate the quality of the evidence on which the recommendations were based. Given the impossibility of obtaining a high level of evidence for most of the recommendations, it was decided to adopt a "Recommendations for Professional Practice" (RPP) format, rather than a Formalized Expert Recommendation (FER) format, and to formulate the recommendations using the terminology of the SFMU and SFAR Guidelines. METHODS: Three fields were defined: 1) pre-hospital assessment, 2) emergency room management, and 3) emergency room discharge modalities. The group assessed 11 questions related to mild traumatic brain injury. Each question was formulated using a PICO (Patients Intervention Comparison Outcome) format. RESULTS: The experts' synthesis work and the application of the GRADE® method resulted in the formulation of 14 recommendations. After two rounds of rating, strong agreement was obtained for all recommendations. For one question, no recommendation could be made. CONCLUSION: There was strong agreement among the experts on important, transdisciplinary recommendations, the purpose of which is to improve management practices for patients with mild head injury.

IMPDHII protein inhibits Toll-like receptor 2-mediated activation of NF-kappaB.

Toll-like receptor 2 (TLR2) plays an essential role in innate immunity by the recognition of a large variety of pathogen-associated molecular patterns. It induces its recruitment to lipid rafts induces the formation of a membranous activation cluster necessary to enhance, amplify, and control downstream signaling. However, the exact composition of the TLR2-mediated molecular complex is unknown. We performed a proteomic analysis in lipopeptide-stimulated THP1 and found IMPDHII protein rapidly recruited to lipid raft. Whereas IMPDHII is essential for lymphocyte proliferation, its biologic function within innate immune signal pathways has not been established yet. We report here that IMPDHII plays an important role in the negative regulation of TLR2 signaling by modulating PI3K activity. Indeed, IMPDHII increases the phosphatase activity of SHP1, which participates to the inactivation of PI3K.