Cédric Laouénan

Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea

Background Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies. Methods and Findings Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age ≥ 1 y, weight ≥ 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in “cycle threshold” [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A “target value” of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%–32.4%) in Group A Ct ≥ 20 and 91% (95% CI 78.8%–91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was ≥110 μmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 μmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 μmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 μmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated. Conclusions In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia. Trial registration ClinicalTrials.gov NCT02329054

Predictive factors of early mortality after transcatheter aortic valve implantation: individual risk assessment using a simple score

Objective Decision making for intervention in symptomatic aortic stenosis should balance the risks of surgery and of transcatheter aortic valve implantation (TAVI). We identified the factors associated with early mortality after TAVI and aimed to develop and validate a simple risk score. Methods A population of 3833 consecutive patients was randomly split into two cohorts comprising 2552 and 1281 patients, used respectively to develop and validate a scoring system predicting 30-day or in-hospital mortality. Results TAVI was performed using the Edwards Sapien prosthesis in 2551 (66.8%) patients and the Medtronic Corevalve in 1270 (33.2%). Approach was transfemoral in 2801 (73.4%) patients, transapical in 678 (17.8%), subclavian in 219 (5.7%) and other in 117 (3.1%). Early mortality was 10.0% (382 patients). A multivariate logistic model identified the following predictive factors of early mortality: age ≥90 years, body mass index <30 Kg/m2, New York Heart Association class IV, pulmonary hypertension, critical haemodynamic state, ≥2 pulmonary oedemas during the last year, respiratory insufficiency, dialysis and transapical or other (transaortic and transcarotid) approaches. A 21-point predictive score was derived. C-index was 0.67 for the score in the development cohort and 0.59 in the validation cohort. There was a good concordance between predicted and observed 30-day mortality rates in the development and validation cohorts. Conclusions Early mortality after TAVI is mainly related to age, the severity of symptoms, comorbidities and transapical approach. A simple score can be used to predict early mortality after TAVI. The moderate discrimination is however a limitation for the accurate identification of high-risk patients.

Phylogenetic Distribution of CTX-M- and Non-Extended-Spectrum-β-Lactamase-Producing Escherichia coli Isolates: Group B2 Isolates, Except Clone ST131, Rarely Produce CTX-M Enzymes

ABSTRACT Escherichia coli is the species most frequently associated with clinical infections by extended-spectrum-β-lactamase (ESBL)-producing isolates, with the CTX-M ESBL enzymes being predominant and found in genetically diverse E. coli isolates. The main objective of this study was to compare, on the basis of a case-control design, the phylogenetic diversity of 152 CTX-M-producing and 152 non-ESBL-producing clinical E. coli isolates. Multilocus sequence typing revealed that even though CTX-M enzymes were largely disseminated across the diversity of E. coli isolates, phylogenetic group B2 showed a particularly heterogeneous situation. First, clone ST131 of group B2 was strongly associated with CTX-M production (55 [79%] of 70 isolates), with CTX-M-15 being predominant. Second, the remaining members of group B2 were significantly less frequently associated with CTX-M production (9 [12%] of 75) than E. coli phylogenetic groups A, B1, and D (88 [55%] of 159). CTX-M-producing ST131 E. coli isolates were significantly more frequent in patients hospitalized in geriatric wards or long-term care facilities. Besides, the non-ESBL ST131 isolates significantly more frequently showed resistance to penicillins than the non-ESBL, non-ST131 isolates did. In conclusion, the present study emphasizes the particular antimicrobial resistance and epidemiologic characteristics of clone ST131 within group B2, which could result from the higher antibiotic exposure of this clone, as it is the predominant clone of group B2 carried in the human gut.

Late Results of Percutaneous Mitral Commissurotomy up to 20 Years: Development and Validation of a Risk Score Predicting Late Functional Results from a Series of 912 Patients

Background— Long-term follow-up after percutaneous mitral commissurotomy enables predictive factors of late results to be identified. Methods and Results— Late results of percutaneous mitral commissurotomy were assessed in 1024 consecutive patients. Good immediate results, defined as valve area ≥1.5 cm2 without mitral regurgitation >2/4, were obtained in 912 patients (89%). These 912 patients were randomly split into 2 cohorts comprising 609 and 303 patients that were used to develop and validate, respectively, a scoring system predicting late functional results. The 20-year rate of good functional results (survival without cardiovascular death, mitral surgery, or repeat percutaneous mitral commissurotomy and in New York Heart Association class I or II) was 30.2±2.0%. A multivariable Cox model identified 7 predictive factors of poor late functional results: higher final mean gradient ( P <0.0001), interaction between age and final mitral valve area ( P <0.0001) showing that the impact of valve area decreases with age, interaction between sex and valve calcification ( P <0.0001) showing that the impact of valve anatomy is stronger in men, and interaction between rhythm and New York Heart Association class showing an impact of New York Heart Association class only in patients in atrial fibrillation ( P <0.0001). A 13-point score enabled 3 risk groups to be defined, corresponding to predicted good functional results of 55.1%, 29.1%, and 10.5% at 20 years in the validation cohort. Conclusions— Twenty years after percutaneous mitral commissurotomy in a population of patients with varied characteristics, 30% still had good functional results. Prediction of late functional results is multifactorial and strongly determined by age and the quality of immediate results. A simple validated scoring system is useful for estimating individual patient outcome. # Clinical Perspective {#article-title-40}Background— Long-term follow-up after percutaneous mitral commissurotomy enables predictive factors of late results to be identified. Methods and Results— Late results of percutaneous mitral commissurotomy were assessed in 1024 consecutive patients. Good immediate results, defined as valve area ≥1.5 cm2 without mitral regurgitation >2/4, were obtained in 912 patients (89%). These 912 patients were randomly split into 2 cohorts comprising 609 and 303 patients that were used to develop and validate, respectively, a scoring system predicting late functional results. The 20-year rate of good functional results (survival without cardiovascular death, mitral surgery, or repeat percutaneous mitral commissurotomy and in New York Heart Association class I or II) was 30.2±2.0%. A multivariable Cox model identified 7 predictive factors of poor late functional results: higher final mean gradient (P<0.0001), interaction between age and final mitral valve area (P<0.0001) showing that the impact of valve area decreases with age, interaction between sex and valve calcification (P<0.0001) showing that the impact of valve anatomy is stronger in men, and interaction between rhythm and New York Heart Association class showing an impact of New York Heart Association class only in patients in atrial fibrillation (P<0.0001). A 13-point score enabled 3 risk groups to be defined, corresponding to predicted good functional results of 55.1%, 29.1%, and 10.5% at 20 years in the validation cohort. Conclusions— Twenty years after percutaneous mitral commissurotomy in a population of patients with varied characteristics, 30% still had good functional results. Prediction of late functional results is multifactorial and strongly determined by age and the quality of immediate results. A simple validated scoring system is useful for estimating individual patient outcome.

Electronic sensors for assessing interactions between healthcare workers and patients under airborne precautions.

Background Direct observation has been widely used to assess interactions between healthcare workers (HCWs) and patients but is time-consuming and feasible only over short periods. We used a Radio Frequency Identification Device (RFID) system to automatically measure HCW-patient interactions. Methods We equipped 50 patient rooms with fixed sensors and 111 HCW volunteers with mobile sensors in two clinical wards of two hospitals. For 3 months, we recorded all interactions between HCWs and 54 patients under airborne precautions for suspected (n = 40) or confirmed (n = 14) tuberculosis. Number and duration of HCW entries into patient rooms were collected daily. Concomitantly, we directly observed room entries and interviewed HCWs to evaluate their self-perception of the number and duration of contacts with tuberculosis patients. Results After signal reconstruction, 5490 interactions were recorded between 82 HCWs and 54 tuberculosis patients during 404 days of airborne isolation. Median (interquartile range) interaction duration was 2.1 (0.8–4.4) min overall, 2.3 (0.8–5.0) in the mornings, 1.8 (0.8–3.7) in the afternoons, and 2.0 (0.7–4.3) at night (P<10−4). Number of interactions/day/HCW was 3.0 (1.0–6.0) and total daily duration was 7.6 (2.4–22.5) min. Durations estimated from 28 direct observations and 26 interviews were not significantly different from those recorded by the network. Conclusions The RFID was well accepted by HCWs. This original technique holds promise for accurately and continuously measuring interactions between HCWs and patients, as a less resource-consuming substitute for direct observation. The results could be used to model the transmission of significant pathogens. HCW perceptions of interactions with patients accurately reflected reality.

Risk factors for postoperative pneumonia after cardiac surgery and development of a preoperative risk score

Objectives:The aims of this study were, first, to identify risk factors for microbiology-proven postoperative pneumonia after cardiac surgery and, second, to develop and validate a preoperative scoring system for the risk of postoperative pneumonia. Design and Setting:A single-center cohort study. Patients:All consecutive patients undergoing cardiac surgery between January 2006 and July 2011. Interventions:None. Measurements and Main Results:Multivariate analysis of risk factors for postoperative pneumonia was performed on data from patients operated between January 2006 and December 2008 (training set). External temporal validation was performed on data from patients operated between January 2009 and July 2011 (validation set). Preoperative variables identified in multivariate analysis of the training set were then used to develop a preoperative scoring system that was validated on the validation set. Postoperative pneumonia occurred in 174 of the 5,582 patients (3.1%; 95% CI, 2.7–3.6). Multivariate analysis identified four risk factors for postoperative pneumonia: age (odds ratio, 1.02; 95% CI, 1.01–1.03), chronic obstructive pulmonary disease (odds ratio, 2.97; 95% CI, 1.8–4.71), preoperative left ventricular ejection fraction (odds ratio, 0.98; 95% CI, 0.96–0.99), and the interaction between RBC transfusion during surgery and duration of cardiopulmonary bypass (odds ratio, 2.98; 95% CI, 1.96–4.54). A 6-point score including the three preoperative variables then defined two risk groups corresponding to postoperative pneumonia rates of 1.8% (score < 3) and 6.5% (score ≥ 3). Conclusion:Assessing preoperative risk factors for postoperative pneumonia with the proposed scoring system could help to implement a preventive policy in high-risk patients with a risk of postoperative pneumonia greater than 4% (i.e., patients with a score ≥3).

Escherichia coli bacteremia in children: age and portal of entry are the main predictors of severity.

Background: Escherichia coli bacteremia is a major cause of severe sepsis in children. Little is known about predictors of severity. Methods: We analyzed 84 children ⩽18 years of age with E. coli bacteremia from the prospective COLIBAFI study performed during 2005–2007. The severity of bacteremia was defined as occurrence of death or transfer to intensive care unit. Studied characteristics included age, gender, birth weight, history of prematurity, immunodepression, nosocomial infection, portal of entry, phylogenetic group and subgroup belonging, O-type, virulence gene content and antimicrobial susceptibility. We compared bacterial characteristics in urinary- versus digestive-source bacteremia, in children ⩽3 versus >3 month of age, and in children versus adults. We also searched for risk factors of severity. Results: Median age was 2.4 months, 57% males. Most frequent portals of entry were urinary (66.2%) and digestive (19.5%) tracts. Most isolates (63.1%) belonged to B2 phylogroup. Strains in children ⩽3 months of age exhibited more virulence genes, especially neuC and fyuA/irp2, and were less resistant to antibiotics than in children >3 months of age. Comparing community-acquired urinary-source bacteremia between children and adults, we found that bacteremia were less severe in children, whose strains exhibited a specific virulence gene repertoire and had a higher resistance score than in adults. Seventeen children (20.2%) had a severe bacteremia and 8 died. Non-urinary portal of entry and age ⩽3 months of age were the only risk factors associated with severity. Conclusions: E. coli strains responsible for bacteremia exhibit specific characteristics according to age of children. However, host characteristics and portal of entry are the main determinants of severity of E. coli bacteremia in children, as observed in adults.

Different Factors Associated with CTX-M-Producing ST131 and Non-ST131 Escherichia coli Clinical Isolates

Objectives To determine factors associated with CTX-M-producing ST131 Escherichia coli which is the worldwide predominant lineage among CTX-M-producing E. coli isolates. Methods Consecutive inpatients with a clinical sample positive for CTX-M-producing E. coli and considered as cases in a previous 8-month (2008–2009) case-control study performed in ten university hospitals in the Paris area were included in the present sub-population study. Patients with a CTX-M-producing ST131 E. coli clinical isolate were compared with those with a CTX-M-producing non-ST131 E. coli clinical isolate with regard to 66 variables. Variables were first compared using univariate logistic regression, then a multivariate analysis using a backward selection with variables with p-value <0.1 in univariate analysis was carried out. Results Fifty-five patients with a CTX-M-producing ST131 E. coli clinical isolate were compared to 97 patients with a CTX-producing non-ST131 E. coli clinical isolate. Multivariate analysis showed that only previous residence in long term care facilities (OR = 4.4; 95% CI = 1.3–14.7) was positively associated with a CTX-M-producing ST131 E. coli isolate. However, it also showed that regular consumption of poultry products (OR = 0.2; 95% CI = 0.1–0.6), having had at least one device in the preceding 6 months (OR = 0.3; 95% CI = 0.1–0.7) and stay in ICU (OR = 0.2; 95% CI = 0.05–0.8) were negatively associated with isolation of CTX-M-producing ST131 E. coli from clinical samples. Conclusions This study provides more insight into the epidemiological features of ST131 and non-ST131 E. coli producing CTX-M enzymes. It shows, for the first time, that isolation of CTX-M-producing ST131 E. coli from clinical samples is not linked to consumption of various foods and confirms that residence in long term care facilities is a predictor of these isolates.

Cardiovascular Effects of Aldosterone Insight From Adult Carriers of Mineralocorticoid Receptor Mutations

Background—High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results—In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P<0.0001), together with increased salt appetite (1.8-fold; P=0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P=0.001; E/e′, P=0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women. Conclusions—Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling. Clinical Trial Registration—http://www.clinicaltrials.gov; unique identifier: NCT00646828.Background— High plasma aldosterone has deleterious cardiovascular effects that are independent of blood pressure, but the role of the mineralocorticoid receptor remains unclear. Renal pseudohypoaldosteronism type 1 is a rare autosomal-dominant disease caused by NR3C2 loss-of-function mutations, which is characterized by renal salt loss and compensatory high renin and aldo secretion. We aimed to assess the cardiovascular outcomes in adults carrying NR3C2 mutations. Methods and Results— In this case-control study, 39 NR3C2 mutation carriers were compared with sex- and age-paired noncarriers. Patients underwent cardiac and vascular ultrasound, cardiac MRI with gadolinium injection, measurement of pulse wave velocity, extracellular water, 24-hour ambulatory blood pressure, and autonomous nervous system activity. Mutation carriers showed increased aldo and renin plasma levels (4.5- and 1.6-fold, respectively; P <0.0001), together with increased salt appetite (1.8-fold; P =0.002), with normal extracellular water and blood pressure, and no autonomous nervous system activation. Cardiac and vascular parameters were not significantly different between mutation carriers and noncarriers (no left ventricular remodeling or fibrosis, normal left ventricular systolic function, and aorta stiffness). Tissue Doppler showed better diastolic left ventricular function in mutation carriers (e′, P =0.001; E/e′, P =0.003). Mutation carriers had significantly more frequent history of slow body weight recovery at birth, symptomatic hypotension, and miscarriage in women. Conclusions— Despite life-long increase in plasma aldosterone and renin levels, no adverse cardiovascular outcome occurred in pseudohypoaldosteronism type 1, but rather an improved diastolic left ventricular function. This suggests that the cardiovascular consequences of aldosterone excess require full mineralocorticoid receptor signaling. Clinical Trial Registration— ; unique identifier: [NCT00646828][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00646828&atom=%2Fcirccvg%2F6%2F4%2F381.atom

Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach

BackgroundModels of hepatitis C virus (HCV) kinetics are increasingly used to estimate and to compare in vivo drug’s antiviral effectiveness of new potent anti-HCV agents. Viral kinetic parameters can be estimated using non-linear mixed effect models (NLMEM). Here we aimed to evaluate the performance of this approach to precisely estimate the parameters and to evaluate the type I errors and the power of the Wald test to compare the antiviral effectiveness between two treatment groups when data are sparse and/or a large proportion of viral load (VL) are below the limit of detection (BLD).MethodsWe performed a clinical trial simulation assuming two treatment groups with different levels of antiviral effectiveness. We evaluated the precision and the accuracy of parameter estimates obtained on 500 replication of this trial using the stochastic approximation expectation-approximation algorithm which appropriately handles BLD data. Next we evaluated the type I error and the power of the Wald test to assess a difference of antiviral effectiveness between the two groups. Standard error of the parameters and Wald test property were evaluated according to the number of patients, the number of samples per patient and the expected difference in antiviral effectiveness.ResultsNLMEM provided precise and accurate estimates for both the fixed effects and the inter-individual variance parameters even with sparse data and large proportion of BLD data. However Wald test with small number of patients and lack of information due to BLD resulted in an inflation of the type I error as compared to the results obtained when no limit of detection of VL was considered. The corrected power of the test was very high and largely outperformed what can be obtained with empirical comparison of the mean VL decline using Wilcoxon test.ConclusionThis simulation study shows the benefit of viral kinetic models analyzed with NLMEM over empirical approaches used in most clinical studies. When designing a viral kinetic study, our results indicate that the enrollment of a large number of patients is to be preferred to small population sample with frequent assessments of VL.