40 research outputs found

    Breakthrough infections due to SARS-CoV-2 Delta variant: relation to humoral and cellular vaccine responses

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    IntroductionCOVID-19 vaccines are expected to provide effective protection. However, emerging strains can cause breakthrough infection in vaccinated individuals. The immune response of vaccinated individuals who have experienced breakthrough infection is still poorly understood.MethodsHere, we studied the humoral and cellular immune responses of fully vaccinated individuals who subsequently experienced breakthrough infection due to the Delta variant of SARS-CoV-2 and correlated them with the severity of the disease.ResultsIn this study, an effective humoral response alone was not sufficient to induce effective immune protection against severe breakthrough infection, which also required effective cell-mediated immunity to SARS-CoV-2. Patients who did not require oxygen had significantly higher specific (p=0.021) and nonspecific (p=0.004) cellular responses to SARS-CoV-2 at the onset of infection than those who progressed to a severe form.DiscussionKnowing both humoral and cellular immune response could allow to adapt preventive strategy, by better selecting patients who would benefit from additional vaccine boosters.Trial registration numbershttps://clinicaltrials.gov, identifier NCT04355351; https://clinicaltrials.gov, identifier NCT04429594

    NLRP3 activation during S. aureus or E. coli bacteremia and in the course of SARS-CoV-2 infection

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    A la phase précoce d’une infection bactérienne ou virale l’immunité innée est capable de détecter certains motifs microbiens conservés (PAMP) reconnus par des récepteurs dédiés à ces motifs (PRR) permettant ainsi d’amorcer la réaction pro-inflammatoire via différentes voies de signalisation. Les inflammasomes représentent une catégorie de PRR capable de transformer la pro-IL-1β et la pro-IL-18 en cytokines pro-inflammatoires actives ainsi que d’induire une mort cellulaire pro-inflammatoire nommée pyroptose. NLRP3 est l’inflammasome le plus étudié. De nombreuses bactéries et de nombreux virus ont été décrits comme pouvant soit activer soit inhiber l’inflammasome NLRP3 mais l’implication clinique de cette activation ou inhibition, reste pour le moment indéterminée. L’objectif de ma thèse était d’étudier l’implication de l’inflammasome NLRP3 au cours de la bactériémie chez l’homme. L’apparition de l’épidémie de COVID-19 nous a permis d’élargir cette étude à l’infection par le SARS-CoV-2. Le protocole NLRP3-BACT nous a permis de mettre en œuvre un test cellulaire à partir du sang total afin d’évaluer le niveau d’activation de la Caspase-1 dans les monocytes et polynucléaires neutrophiles (PNN) ainsi que le potentiel d’activation de l’inflammasome NLRP3 dans ces cellules chez des patients présentant une bactériémie à S. aureus ou E. coli via une analyse par cytométrie en flux (signal FAM-FLICA).Le protocole CoVinnate avait pour objectif l’utilisation du test cellulaire précédemment mentionné afin de décrire l’activation d’une partie du système immunitaire inné dans les différentes cellules myéloïdes circulantes des patients COVID-19 ainsi que l’évaluation de ce test en tant qu’outil pronostique.Pour NLRP3-BACT 22 patients ont été inclus depuis le début de de l’étude, 16 ont bénéficié d’une analyse cytométrique. Dans cette première série de patients inclus nous avons mis en évidence que les monocytes présentent un potentiel d’activation de la Caspase-1 par Nigéricine+LPS plus important que les donneurs sains. Par ailleurs, l’activation basale de cette caspase dans les monocytes est plus importante chez les patients de réanimation et ceux infectés par E. coli. Enfin la multiplication de la MFI du signal FAM-FLICA induite par Nigéricine+LPS est plus important pour les patients de médecine comparativement aux patients de réanimation.Pour CoVinnate, 66 patients COVID-19 et 24 donneurs sains ont été inclus durant la période de l’étude. Dans les cellules CD66b+ CD16dim nous avons observé une diminution significative du signal de la sonde FAM-FLICA chez les patients les plus sévères comparativement aux témoins. Au sein des granulocytes, l’activation de la Caspase-1 induite par la Nigéricine était altérée dans les granulocytes CD66b+ CD16dim selon le degré de sévérité des patients. Nous avons enregistré une augmentation de l’activation de NLRP3 induite par la Nigéricine dans les monocytes non-classiques isolés chez les patients les plus graves, cet effet était inversement corrélé au nombre total de monocytes non-classiques. Chez les patients les plus sévères on notait une augmentation du nombre de cellules CD66b+CD16dimCD15+CD10- correspondant à des neutrophiles immatures. Nous avons utilisé la diminution des monocytes non-classiques et le défaut d’activation de NLRP3 par la Nigéricine des granulocytes CD66b+ CD16dim pour construire un score pronostique. Nous avons mis en évidence une corrélation entre ce score et le rapport SpO2 / FiO2 le jour de l’inclusion ainsi que 48 heures plus tard. Nous avons également constaté une association significative de ces deux marqueurs avec l’évolution finale des patients. Mon travail a permis de mieux comprendre l’implication de l’inflammasome NLRP3 chez l’homme au cours de la bactériémie et durant l’infection à SARS-CoV-2. Nous envisageons d’utiliser ces travaux pour caractériser la réponse des patients aux traitements immunomodulateurs utilisés dans la COVID-19 notamment les corticoïdes.At the early phase of bacterial or viral infections, innate immunity is able to detect some conserved microbial motifs (PAMP) recognized by receptors dedicated to these motifs (PRR), thus making it possible to initiate the pro-inflammatory reaction via different signaling pathways. Inflammasomes represent a family of PRR able to transform pro-IL-1β and pro-IL-18 into active pro-inflammatory cytokines as well as inducing a pro-inflammatory cell death called pyroptosis. NLRP3 is the most studied inflammasome. Many bacteria and viruses have been described as being able to either activate or inhibit the NLRP3 inflammasome, but the clinical implication of this activation or inhibition, under the control of a particular microorganism, remains undetermined at this time.The objective of my thesis was to study the involvement of the NLRP3 inflammasome during bacteremia in humans. The onset of the COVID-19 epidemic allowed us to expand this study to SARS-CoV-2 infection.The NLRP3-BACT protocol allowed us to implement a cellular test performed on whole blood to assess the level of Caspase-1 activation in monocytes and polymorphonuclear neutrophils (PMN) as well as the activation potential of the NLRP3 inflammasome in these cells in patients with S. aureus or E. coli bacteremia via flow cytometry (fluorescent inhibitor probe, FAM-FLICA).The objective of the CoVinnate protocol was to use the aforementioned cellular test to describe the activation of a part of the innate immune system in the various circulating myeloid cells of COVID-19 patients as well as the evaluation of this test as a prognostic tool.For NLRP3-BACT 22 patients have been included since the start of the study, 16 have undergone cytometric analysis. In this first series of patients included, we demonstrated that monocytes have a greater potential for Caspase-1 activation by Nigericin+LPS than healthy donors. In addition, basal activation of this caspase in monocytes is greater in intensive care patients and in those infected with E. coli compared to the ID ward and S. aureus respectively. Finally, the multiplication of the MFI of the FAM-FLICA signal induced by Nigericin + LPS is more important for medical patients compared to intensive care patients.For CoVinnate, 66 COVID-19 patients and 24 healthy donors were included during the study period. In CD66b+ CD16dim cells, we observed a significant decrease of the FAM-FLICA probe signal in the most severe patients compared to the controls. Within granulocytes, the activation of Caspase-1 induced by Nigericin was decreased in CD66b+ CD16dim cells according to the severity of the patients. We recorded an increase in Nigericin-induced activation of NLRP3 in non-classical monocytes isolated from the most severe patients, this effect was inversely correlated with the total number of non-classical monocytes. In the most severe patients there was an increase in the number of CD66b+CD16dimCD15+CD10- cells corresponding to immature neutrophils.We used the decreased number in non-classical monocytes and the failure of NLRP3 activation upon nigericin activation in CD66b + CD16dim granulocytes to build a prognostic score. We found a correlation between this score and the SpO2 / FiO2 ratio on the day of inclusion as well as 48 hours later. We also found a significant association of these two markers with the final outcome of the patients.My work has led to a better understanding of the involvement of the NLRP3 inflammasome in humans during bacteremia and during SARS-CoV-2 infection. We plan to use this work to characterize the response of patients to immunomodulatory treatments used in COVID-19, including corticosteroids

    Activation de l’inflammasome NLRP3 au cours des bactériémies à E. coli ou S. aureus et durant l’infection à SARS-CoV-2

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    At the early phase of bacterial or viral infections, innate immunity is able to detect some conserved microbial motifs (PAMP) recognized by receptors dedicated to these motifs (PRR), thus making it possible to initiate the pro-inflammatory reaction via different signaling pathways. Inflammasomes represent a family of PRR able to transform pro-IL-1β and pro-IL-18 into active pro-inflammatory cytokines as well as inducing a pro-inflammatory cell death called pyroptosis. NLRP3 is the most studied inflammasome. Many bacteria and viruses have been described as being able to either activate or inhibit the NLRP3 inflammasome, but the clinical implication of this activation or inhibition, under the control of a particular microorganism, remains undetermined at this time.The objective of my thesis was to study the involvement of the NLRP3 inflammasome during bacteremia in humans. The onset of the COVID-19 epidemic allowed us to expand this study to SARS-CoV-2 infection.The NLRP3-BACT protocol allowed us to implement a cellular test performed on whole blood to assess the level of Caspase-1 activation in monocytes and polymorphonuclear neutrophils (PMN) as well as the activation potential of the NLRP3 inflammasome in these cells in patients with S. aureus or E. coli bacteremia via flow cytometry (fluorescent inhibitor probe, FAM-FLICA).The objective of the CoVinnate protocol was to use the aforementioned cellular test to describe the activation of a part of the innate immune system in the various circulating myeloid cells of COVID-19 patients as well as the evaluation of this test as a prognostic tool.For NLRP3-BACT 22 patients have been included since the start of the study, 16 have undergone cytometric analysis. In this first series of patients included, we demonstrated that monocytes have a greater potential for Caspase-1 activation by Nigericin+LPS than healthy donors. In addition, basal activation of this caspase in monocytes is greater in intensive care patients and in those infected with E. coli compared to the ID ward and S. aureus respectively. Finally, the multiplication of the MFI of the FAM-FLICA signal induced by Nigericin + LPS is more important for medical patients compared to intensive care patients.For CoVinnate, 66 COVID-19 patients and 24 healthy donors were included during the study period. In CD66b+ CD16dim cells, we observed a significant decrease of the FAM-FLICA probe signal in the most severe patients compared to the controls. Within granulocytes, the activation of Caspase-1 induced by Nigericin was decreased in CD66b+ CD16dim cells according to the severity of the patients. We recorded an increase in Nigericin-induced activation of NLRP3 in non-classical monocytes isolated from the most severe patients, this effect was inversely correlated with the total number of non-classical monocytes. In the most severe patients there was an increase in the number of CD66b+CD16dimCD15+CD10- cells corresponding to immature neutrophils.We used the decreased number in non-classical monocytes and the failure of NLRP3 activation upon nigericin activation in CD66b + CD16dim granulocytes to build a prognostic score. We found a correlation between this score and the SpO2 / FiO2 ratio on the day of inclusion as well as 48 hours later. We also found a significant association of these two markers with the final outcome of the patients.My work has led to a better understanding of the involvement of the NLRP3 inflammasome in humans during bacteremia and during SARS-CoV-2 infection. We plan to use this work to characterize the response of patients to immunomodulatory treatments used in COVID-19, including corticosteroids.A la phase précoce d’une infection bactérienne ou virale l’immunité innée est capable de détecter certains motifs microbiens conservés (PAMP) reconnus par des récepteurs dédiés à ces motifs (PRR) permettant ainsi d’amorcer la réaction pro-inflammatoire via différentes voies de signalisation. Les inflammasomes représentent une catégorie de PRR capable de transformer la pro-IL-1β et la pro-IL-18 en cytokines pro-inflammatoires actives ainsi que d’induire une mort cellulaire pro-inflammatoire nommée pyroptose. NLRP3 est l’inflammasome le plus étudié. De nombreuses bactéries et de nombreux virus ont été décrits comme pouvant soit activer soit inhiber l’inflammasome NLRP3 mais l’implication clinique de cette activation ou inhibition, reste pour le moment indéterminée. L’objectif de ma thèse était d’étudier l’implication de l’inflammasome NLRP3 au cours de la bactériémie chez l’homme. L’apparition de l’épidémie de COVID-19 nous a permis d’élargir cette étude à l’infection par le SARS-CoV-2. Le protocole NLRP3-BACT nous a permis de mettre en œuvre un test cellulaire à partir du sang total afin d’évaluer le niveau d’activation de la Caspase-1 dans les monocytes et polynucléaires neutrophiles (PNN) ainsi que le potentiel d’activation de l’inflammasome NLRP3 dans ces cellules chez des patients présentant une bactériémie à S. aureus ou E. coli via une analyse par cytométrie en flux (signal FAM-FLICA).Le protocole CoVinnate avait pour objectif l’utilisation du test cellulaire précédemment mentionné afin de décrire l’activation d’une partie du système immunitaire inné dans les différentes cellules myéloïdes circulantes des patients COVID-19 ainsi que l’évaluation de ce test en tant qu’outil pronostique.Pour NLRP3-BACT 22 patients ont été inclus depuis le début de de l’étude, 16 ont bénéficié d’une analyse cytométrique. Dans cette première série de patients inclus nous avons mis en évidence que les monocytes présentent un potentiel d’activation de la Caspase-1 par Nigéricine+LPS plus important que les donneurs sains. Par ailleurs, l’activation basale de cette caspase dans les monocytes est plus importante chez les patients de réanimation et ceux infectés par E. coli. Enfin la multiplication de la MFI du signal FAM-FLICA induite par Nigéricine+LPS est plus important pour les patients de médecine comparativement aux patients de réanimation.Pour CoVinnate, 66 patients COVID-19 et 24 donneurs sains ont été inclus durant la période de l’étude. Dans les cellules CD66b+ CD16dim nous avons observé une diminution significative du signal de la sonde FAM-FLICA chez les patients les plus sévères comparativement aux témoins. Au sein des granulocytes, l’activation de la Caspase-1 induite par la Nigéricine était altérée dans les granulocytes CD66b+ CD16dim selon le degré de sévérité des patients. Nous avons enregistré une augmentation de l’activation de NLRP3 induite par la Nigéricine dans les monocytes non-classiques isolés chez les patients les plus graves, cet effet était inversement corrélé au nombre total de monocytes non-classiques. Chez les patients les plus sévères on notait une augmentation du nombre de cellules CD66b+CD16dimCD15+CD10- correspondant à des neutrophiles immatures. Nous avons utilisé la diminution des monocytes non-classiques et le défaut d’activation de NLRP3 par la Nigéricine des granulocytes CD66b+ CD16dim pour construire un score pronostique. Nous avons mis en évidence une corrélation entre ce score et le rapport SpO2 / FiO2 le jour de l’inclusion ainsi que 48 heures plus tard. Nous avons également constaté une association significative de ces deux marqueurs avec l’évolution finale des patients. Mon travail a permis de mieux comprendre l’implication de l’inflammasome NLRP3 chez l’homme au cours de la bactériémie et durant l’infection à SARS-CoV-2. Nous envisageons d’utiliser ces travaux pour caractériser la réponse des patients aux traitements immunomodulateurs utilisés dans la COVID-19 notamment les corticoïdes

    Patients with community-acquired bacteremia of unknown origin: clinical characteristics and usefulness of microbiological results for therapeutic issues: a single-center cohort study

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    Abstract Bacteremia of unknown origin (BUO) are associated with increased mortality compared to those with identified sources. Microbiological data of those patients could help to characterize an appropriate empirical antibiotic treatment before bloodcultures results are available during sepsis of unknown origin. Based on the dashboard of our ward that prospectively records several parameters from each hospitalization, we report 101 community-acquired BUO selected among 1989 bacteremic patients from July 2005 to April 2016, BUO being defined by the absence of clinical and paraclinical infectious focus and no other microbiological samples retrieving the bacteria isolated from blood cultures. The in-hospital mortality rate was 9%. We retrospectively tested two antibiotic associations: amoxicillin–clavulanic acid + gentamicin (AMC/GM) and 3rd generation cephalosporin + gentamicin (3GC/GM) considered as active if the causative bacteria was susceptible to at least one of the two drugs. The mean age was 71 years with 67% of male, 31 (31%) were immunocompromised and 52 (51%) had severe sepsis. Eleven patients had polymicrobial infections. The leading bacterial species involved were Escherichia coli 25/115 (22%), group D Streptococci 12/115 (10%), viridans Streptococci 12/115 (10%) and Staphylococcus aureus 11/115 (9%). AMC/GM displayed a higher rate of effectiveness compared to 3GC/GM: 100/101 (99%) vs 94/101 (93%) (p = 0.04): one Enterococcus faecium strain impaired the first association, Bacteroides spp. and Enterococcus spp. the second. In case of community-acquired sepsis of unknown origin, AMC + GM should be considered

    Time-to-detection in culture of Mycobacterium tuberculosis: performance for assessing index cases contact-positivity

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    Objectives: Time-to-detection (TTD) in culture on liquid media is inversely correlated to bacillary load and should be a contributing factor for assessing tuberculosis transmission. We wanted to assess if TTD was a better alternative than smear status to estimate transmission risk. Methods: From October 2015 to June 2022, we retrospectively studied a cohort of index cases (IC) with pulmonary tuberculosis (tuberculosis disease [TD]) from which samples were culture-positive before treatment. We studied the correlation between TTD and contact-positivity (CP) of IC contacts: CP was defined as CP = 1 (CP group) in case of TD or latent tuberculosis infection (LTI) in at least one screened contact of an IC, and CP = 0 otherwise (contact-negativity [CN] group). Univariate and multivariable analyses (logistic regression) were done. Results: Of the 185 IC, 122 were included, generating 846 contact cases of which 705 were assessed. A transmission event (LTI or TD) was identified in 193 contact cases (transmission rate: 27%). At day 9, 66% and 35% of the IC had their sample positive in culture for CP and CN groups, respectively. Age and TTD ≤9 days were independent criteria of CP (odds ratio 0.97, confidence interval [0.95-0.98], P = 0.002 and odds ratio 3.52, confidence interval [1.59-7.83], P = 0.001, respectively). Conclusion: TTD was a more discriminating parameter than smear status to evaluate the transmission risk of an IC with pulmonary tuberculosis. Therefore, TTD should be considered in the contact-screening strategy around an IC

    Clindamycin Efficacy for <i>Cutibacterium acnes</i> Shoulder Device-Related Infections

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    Clindamycin is an antibiotic with high bioavailability and appropriate bone diffusion, often proposed as an alternative in guidelines for C. acnes prosthetic joint infections. We aimed to evaluate the efficacy of clindamycin in the treatment of C. acnes shoulder implant joint infections (SIJI). Methods: A retrospective analysis was conducted at the University Hospital of Nice (France) between 2010 and 2019. We included patients with one shoulder implant surgical procedure and at least one C. acnes positive sample. We selected the C. acnes SIJI according to French and international recommendations. The primary endpoint was favorable outcome of C. acnes SIJI treatment after at least 1-year follow-up in the clindamycin group compared to another therapeutic group. Results: Forty-eight SIJI were identified and 33 were treated with clindamycin, among which 25 were treated with monotherapy. The median duration of clindamycin antibiotherapy was 6 weeks. The average follow-up was 45 months; one patient was lost to follow-up. Twenty-seven patients out of 33 (82%) were cured with clindamycin, compared to 9/12 (75%) with other antibiotics. The rate of favorable outcomes increased to 27/31 (87%) with clindamycin and to 9/10 (90%) for other antibiotics when no septic revision strategies were excluded (P = 1.00). Conclusions: The therapeutic strategy based on one- or two-stage revision associated with 6 weeks of clindamycin seems to be effective

    Effectiveness and safety of dalbavancin in France: a prospective, multicentre cohort study

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    International audienceOBJECTIVES: Dalbavancin is a lipoglycopeptide antibiotic approved for the treatment of acute bacterial skin and skin structure infections. However, several studies have suggested that it is used mostly for off-label indications. We aimed to describe the use of dalbavancin in patients who received at least one dose of the antibiotic in France. METHODS: Prospective, observational, multicentre study conducted in France from September 2018 to April 2020. The primary outcome was the clinical response at 30 days after the last dalbavancin dose. RESULTS: A total of 151 patients in 16 centres were included in this study. The main infection sites were bone and joint infections (55.0%), multisite infections (15.9%), and vascular infections (14.6%), and the primary pathogens were coagulase-negative staphylococci (N = 82), Staphylococcus aureus (N = 51), and enterococci (N = 27). Most patients (71.5%) received three previous antibiotic treatments. The number of dalbavancin injections per patient was 1 in 26 patients (17.2%), 2 in 95 patients (62.9%), 3 in 17 patients (11.3%), and more than 3 in 13 patients (8.6%), with a mean cumulative dose of 3089 ± 1461 mg per patient. Among the 129 patients with a complete follow-up, clinical success was achieved in 119 patients (92.2%). At least 1 adverse event was reported in 67 patients (44.4%), including 12 (7.9%) patients with dalbavancin-related adverse events. CONCLUSIONS: The results of the study showed that dalbavancin is used mostly for off-label indications and in heavily pretreated patients in France. The clinical response at 30 days after the last dose was favourable in most patients, with a good safety profile

    Management of prosthetic joint infections in France: a national audit to identify key situations requiring innovation and homogenization

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    International audienceBackground: Prosthetic joint infections (PJI) are one of the most serious complication of arthroplasty. The management of PJI needs a multidisciplinary collaboration between orthopaedic surgeon, infectious disease specialist and microbiologist. In France, the management of PJI is organized around reference centres (CRIOACs). Our main objective was to perform an audit through a questionnaire survey based on clinical cases, to evaluate how French physicians manage PJI. Eligible participants were all physicians involved in care of patients presenting a PJI. Physicians could answer individually, or collectively during a multidisciplinary team meeting dedicated to PJI. The survey consisted as three questionnaires organized in a total of six clinical cases. Results: Answers from the CRIOACs to the three questionnaires were 92, 77, and 53%. Between 32 and 39% of respondents did not administer antibiotic prophylaxis despite positive S. aureus pre-operative documentation. One-stage exchange strategy was widely preferred in all clinical cases, with no difference between CRIOACs and other centres. Rifampicin was prescribed for S. aureus PJI, in a situation with (90-92%) or without any prosthesis (70%). There was no consensus for the total antibiotic regimen duration, with prescriptions from six to 12 weeks for a majority of respondents. Conclusions: Surgical strategy for the management of PJI was homogenous with a preference for a onestage exchange strategy. Medical management was more heterogenous, which reflects the heterogeneity of those infections and difficulties to perform studies with strong conclusions

    Pyogenic vertebral osteomyelitis of the elderly: Characteristics and outcomes

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    <div><p>Background</p><p>The incidence of pyogenic vertebral osteomyelitis (PVO) has increased over the past two decades. One possible cause of this increase is the aging of the population, which results in more comorbidities in high income countries.</p><p>Objective</p><p>To better characterize the clinical presentation and outcome of PVO in the elderly.</p><p>Design</p><p>We conducted a post-hoc analysis of a previously published trial that studied treatment duration in PVO and compared the presentation and outcomes according to age.</p><p>Participants</p><p>Our analysis included 351 patients among whom 85 (24%) were 75-years-old or more.</p><p>Results</p><p>There were no significant differences in the socio-demographics of the patients. Neoplasia and chronic inflammatory diseases were more common in the older group: 34% vs. 19% (p = 0.021) and 9% versus 1% (p = 0.004), respectively. There were no significant differences in clinical and radiological presentations between the groups in terms of back pain (337/351, 97%), fever (182/351, 52%), PVO localization, neurological signs and epidural abscess. Associated infective endocarditis (IE) was more frequent in the older group (37% vs. 14%, p<0.001). Streptococci were more frequently involved in infections of older patients (29% vs. 14%, p = 0.003) in contrast to Staphylococcus aureus (31% vs. 45%, p = 0.03). Older patients displayed higher mortality rates at 1 year (21% vs. 3%, p<0.001) and more adverse events related to cardiorespiratory failure (10.6% vs. 3.8%, p = 0.025), but had similar quality of life among the survivors.</p><p>Conclusion</p><p>During PVO, the clinical and radiological findings are similar in older patients. Global mortality rates are higher in older patients compared to younger patients, which could be explained by the increased frequency of neoplasia at diagnosis and higher prevalence of associated IE in the elderly.</p></div
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