Antibiotic prophylaxis for the prevention of infective endocarditis for dental procedures is not associated with fatal adverse drug reactions in France

One of the major reasons to stop antibiotic prophylaxis (AP) to prevent infective endocarditis (IE) in the United Kingdom but not in the rest of the world was that it would result in more deaths from fatal adverse drug reactions (ADRs) than the number of IE deaths. The main aim of this study was to quantify and describe the ADRs with amoxicillin or clindamycin for IE AP. The second aim was to infer a crude incidence of anaphylaxis associated with amoxicillin for IE AP. The Medical Dictionary for Regulatory Activities (MedDRA) was used to group ADRs for IE AP using the broad Standardized MedDRA Queries ?Anaphylactic reaction, Amoxicillin, Clindamycin, Clostridium Difficile infection? to the French Pharmacovigilance Database System. From this first-line collection, we selected all cases occurring for IE AP and ultimately, the cases for IE AP for a dental procedure. Then, each case was analyzed. Of 11639 first-line recorded ADRs, 100 were for IE AP but no fatal anaphylaxis to amoxicillin or clindamycin and no C. difficile infection associated with clindamycin were identified. Only 17 cases of anaphylaxis to amoxicillin related to dental procedures were highlighted. The estimation of the crude incidence rate of anaphylaxis associated with amoxicillin for IE AP for invasive dental procedure was 1/57 000 (95% CI 0.2-0.6). Fatal or severe ADRs with amoxicillin or clindamycin is not a rational argument to stop IE AP before invasive dental procedures

Staphylococcus aureus infective endocarditis versus bacteremia strains: Subtle genetic differences at stake

AbstractInfective endocarditis (IE)(1) is a severe condition complicating 10–25% of Staphylococcus aureus bacteremia. Although host-related IE risk factors have been identified, the involvement of bacterial features in IE complication is still unclear. We characterized strictly defined IE and bacteremia isolates and searched for discriminant features. S. aureus isolates causing community-acquired, definite native-valve IE (n=72) and bacteremia (n=54) were collected prospectively as part of a French multicenter cohort. Phenotypic traits previously reported or hypothesized to be involved in staphylococcal IE pathogenesis were tested. In parallel, the genotypic profiles of all isolates, obtained by microarray, were analyzed by discriminant analysis of principal components (DAPC)(2). No significant difference was observed between IE and bacteremia strains, regarding either phenotypic or genotypic univariate analyses. However, the multivariate statistical tool DAPC, applied on microarray data, segregated IE and bacteremia isolates: IE isolates were correctly reassigned as such in 80.6% of the cases (C-statistic 0.83, P<0.001). The performance of this model was confirmed with an independent French collection IE and bacteremia isolates (78.8% reassignment, C-statistic 0.65, P<0.01). Finally, a simple linear discriminant function based on a subset of 8 genetic markers retained valuable performance both in study collection (86.1%, P<0.001) and in the independent validation collection (81.8%, P<0.01). We here show that community-acquired IE and bacteremia S. aureus isolates are genetically distinct based on subtle combinations of genetic markers. This finding provides the proof of concept that bacterial characteristics may contribute to the occurrence of IE in patients with S. aureus bacteremia

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Infective endocarditis : from risk assessment to prevention, using a cohort study and a medico-administrative database

L’endocardite infectieuse (EI) est une maladie rare, de diagnostic difficile et de pronostic réservé. Staphylococcus aureus (SA) et les streptocoques oraux en sont les principaux microorganismes responsables. L’évaluation du risque de survenue de l’EI et l’amélioration des connaissances justifiant la stratégie de prévention nécessitent la mise en place de grandes cohortes cliniques et l’utilisation de bases médico-administratives. Chez les 2 008 patients (pts) présentant une bactériémie à SA de la cohorte multicentrique nationale VIRSTA, nous avons développé et validé un score prédictif d’EI comportant les caractéristiques initiales des pts et celles initiales et évolutives de la bactériémie. Les pts dont le score était ≤ 2 avaient un très faible risque d’EI (1% ; valeur prédictive négative [IC95%] = 99% [98;99]) comparés à ceux dont le score était ≥ 3, à risque d’EI élevé (17%) pour lesquels une échocardiographie devrait être effectuée. Utilisant la base médico-administrative du SNIIRAM, nous avons évalué la relation entre la pratique de gestes buccodentaires invasifs (GBDI) et la survenue d’EI à streptocoques oraux à partir d’une cohorte de 138 876 porteurs de prothèses valvulaires cardiaques ainsi que d’un plan expérimental de type case-crossover incluant 648 EI à streptocoques oraux. L’incidence d’EI à streptocoques oraux [IC95%] était de 93,7 pour 100 000 PA [82,4;104,9] sans augmentation significative du risque dans les 3 mois suivant un GBDI (RR= 1,25 [0,82;1,82]). Dans l’analyse case-crossover, la fréquence d’exposition à un GBDI dans les 3 mois précédent l’EI était faible mais plus élevée que lors de périodes contrôles antérieures (5,1% vs 3,2% ; OR : 1,66 [1,05;2,63]). Les GBDI pourraient contribuer au développement des EI à streptocoques oraux dans la population de pts porteurs de prothèses valvulaires cardiaques.La qualité des données de VIRSTA associée à la puissance du SNIIRAM ont permis l’identification des pts à risque d’EI à SA et la clarification de la contribution des GBDI dans les EI à streptocoques oraux.Infective endocarditis (IE) is a rare disease, difficult to diagnose, with high morbidity and mortality rates. Main involved microorganisms are Staphylococcus aureus and oral streptococci. Clinical research to improve IE risk assessment and IE prevention strategy requires the establishment of large clinical cohort studies and the use of medico-administrative databases. Using data from the multicenter French prospective VIRSTA cohort study on 2 008 adult patients (pts) with Staphylococcus aureus bloodstream infection (SAB), we have developed and validated an IE prediction score taking into account pts’ background and initial SAB characteristics. Pts with a score ≤ 2 had a very low risk of IE (1%, negative predictive value [95% CI] = 99% [98;99]) compared to those with a score ≥ 3, at higher risk of IE (17%) for whom an echocardiography is needed. Using the medico-administrative SNIIRAM database, we assessed the relation between invasive dental procedures (IDP) and oral streptococcal IE in a population-based cohort study of 138 876 pts with prosthetic heart valves and a case-crossover study including 648 pts with oral streptococcal IE. Incidence rate of oral streptococcal IE [95% CI] was 93.7 per 100 000 PA [82.4;104.9] without significant increase within the 3 months following IDP (RR = 1.25 [0.82;1.82]). In the case-crossover analysis, exposure to IDP was more frequent in the 3 months preceding IE than during previous control periods (5.1% vs. 3.2%, OR: 1.66 [1.05;2.63]). IDP may contribute to the development of oral streptococcal IE in pts with prosthetic heart valves.The quality of data from VIRSTA study combined with the power of SNIIRAM database made possible the identification of IE at-risk SAB pts and the evaluation of the IDP contribution in oral streptococcal IE

Endocardite infectieuse : du risque à la prévention, de la cohorte clinique à la base médico-administrative

Infective endocarditis (IE) is a rare disease, difficult to diagnose, with high morbidity and mortality rates. Main involved microorganisms are Staphylococcus aureus and oral streptococci. Clinical research to improve IE risk assessment and IE prevention strategy requires the establishment of large clinical cohort studies and the use of medico-administrative databases. Using data from the multicenter French prospective VIRSTA cohort study on 2 008 adult patients (pts) with Staphylococcus aureus bloodstream infection (SAB), we have developed and validated an IE prediction score taking into account pts’ background and initial SAB characteristics. Pts with a score ≤ 2 had a very low risk of IE (1%, negative predictive value [95% CI] = 99% [98;99]) compared to those with a score ≥ 3, at higher risk of IE (17%) for whom an echocardiography is needed. Using the medico-administrative SNIIRAM database, we assessed the relation between invasive dental procedures (IDP) and oral streptococcal IE in a population-based cohort study of 138 876 pts with prosthetic heart valves and a case-crossover study including 648 pts with oral streptococcal IE. Incidence rate of oral streptococcal IE [95% CI] was 93.7 per 100 000 PA [82.4;104.9] without significant increase within the 3 months following IDP (RR = 1.25 [0.82;1.82]). In the case-crossover analysis, exposure to IDP was more frequent in the 3 months preceding IE than during previous control periods (5.1% vs. 3.2%, OR: 1.66 [1.05;2.63]). IDP may contribute to the development of oral streptococcal IE in pts with prosthetic heart valves.The quality of data from VIRSTA study combined with the power of SNIIRAM database made possible the identification of IE at-risk SAB pts and the evaluation of the IDP contribution in oral streptococcal IE.L’endocardite infectieuse (EI) est une maladie rare, de diagnostic difficile et de pronostic réservé. Staphylococcus aureus (SA) et les streptocoques oraux en sont les principaux microorganismes responsables. L’évaluation du risque de survenue de l’EI et l’amélioration des connaissances justifiant la stratégie de prévention nécessitent la mise en place de grandes cohortes cliniques et l’utilisation de bases médico-administratives. Chez les 2 008 patients (pts) présentant une bactériémie à SA de la cohorte multicentrique nationale VIRSTA, nous avons développé et validé un score prédictif d’EI comportant les caractéristiques initiales des pts et celles initiales et évolutives de la bactériémie. Les pts dont le score était ≤ 2 avaient un très faible risque d’EI (1% ; valeur prédictive négative [IC95%] = 99% [98;99]) comparés à ceux dont le score était ≥ 3, à risque d’EI élevé (17%) pour lesquels une échocardiographie devrait être effectuée. Utilisant la base médico-administrative du SNIIRAM, nous avons évalué la relation entre la pratique de gestes buccodentaires invasifs (GBDI) et la survenue d’EI à streptocoques oraux à partir d’une cohorte de 138 876 porteurs de prothèses valvulaires cardiaques ainsi que d’un plan expérimental de type case-crossover incluant 648 EI à streptocoques oraux. L’incidence d’EI à streptocoques oraux [IC95%] était de 93,7 pour 100 000 PA [82,4;104,9] sans augmentation significative du risque dans les 3 mois suivant un GBDI (RR= 1,25 [0,82;1,82]). Dans l’analyse case-crossover, la fréquence d’exposition à un GBDI dans les 3 mois précédent l’EI était faible mais plus élevée que lors de périodes contrôles antérieures (5,1% vs 3,2% ; OR : 1,66 [1,05;2,63]). Les GBDI pourraient contribuer au développement des EI à streptocoques oraux dans la population de pts porteurs de prothèses valvulaires cardiaques.La qualité des données de VIRSTA associée à la puissance du SNIIRAM ont permis l’identification des pts à risque d’EI à SA et la clarification de la contribution des GBDI dans les EI à streptocoques oraux

Évènements indésirables associés aux soins en milieu hospitalier (illustration à partir d'une enquête transversale de prévalence dans un centre hospitalo-universitaire parisien)

La gestion des risques iatrogènes est un enjeu de santé publique majeur. Peu de données sur les évènements indésirables associés aux soins (EIAS) sont disponibles, ce qui nous a conduits à évaluer leur prévalence au sein d un centre hospitalier universitaire, à proposer une nouvelle approche de classification et à identifier des groupes de patients à risque. Une enquête transversale de prévalence un jour donné a été menée dans les services volontaires. Parmi les 429 patients inclus, 105 ont présenté un ou plusieurs EIAS, soit une prévalence de 24,5% (IC95% 20,4-28,6). Les infections nosocomiales représentaient un tiers des EIAS. Le risque d EIAS était indépendamment associé au nombre de dispositifs médicaux utilisés (P<0,01), à la durée d hospitalisation (p<0,01) et à une hospitalisation en réanimation (p=0,04). Même si tous les EIAS ne sont pas évitables, cette enquête pilote souligne l importance de renforcer les mesures destinées à améliorer la sécurité des soins.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Echocardiography in Patients With Enterococcal Bacteremia

International audienc