A new coronavirus, called SARS-CoV-2, was identified in Wuhan, China, in December 2019. The SARS-CoV-2 spread very rapidly, causing a global pandemic, Coronavirus Disease 2019 (COVID-19). Older adults have higher peak of viral load and, especially those with comorbidities, had higher COVID-19-related fatality rates than younger adults. In this Perspective paper, we summarize current knowledge about SARS-CoV-2 and aging, in order to understand why older people are more affected by COVID-19. We discuss about the possibility that the so-called "immunosenescence" and "inflammaging" processes, already present in a fraction of frail older adults, could allow the immune escape of SARS-CoV-2 leading to COVID-19 serious complications. Finally, we propose to use geroscience approaches to the field of COVID-19.
Abstract Background The antibiotic management of staphylococcal bone and joint infection usually relies on rifampin associated with another antibiotic for susceptible strains. The appropriate dose of rifampin remains unclear and diverges in international recommendations. 543 patients were randomized, 530 were included in the Intent-to-Treat analysis and 327 in the per-protocol analysis. Methods We performed an open-label, randomized, controlled, noninferiority trial to compare a daily dose of 10 mg/kg (Low-dose) qd and 20 mg/kg (High-dose, divided in 10mg/kg bid for high BMIs) of rifampin in association with another antibiotic in patients with microbiologically confirmed bone and joint infections due to Staphylococcus sp. Surgical procedures were performed as needed. The primary outcome was persistent infection, defined as the persistence or recurrence of infection with the initial causative bacteria within 1 year after the completion of antibiotic therapy. Results A total of 543 patients from 18 French centers were randomly assigned to receive either Low-dose (252 patients) or High-dose (291 patients) of rifampin associated with another antibiotic. Thirteen patients who withdrew consent were not included in the analysis. The main antibiotics associated with rifampin were levofloxacin/ofloxacin (82%, 435 out of 530 patients). Mean age was 59.8 ± 16.4 years, and mean BMI 27.9 ± 5.8 kg/m2; 24.6% [n=130] had osteosynthesis and 34% [n=180] prostheses at the site of infection. Staphylococcus aureus was present in 75.8% of patients [n=402]. In the ITT analysis, persistent infection occurred in 8 of 227 patients (3.5%) in the Low-dose group and in 10 of 265 patients (3,8%) in the High-dose group (risk difference, 0.0019; 95% confidence interval [-0.032 – 0.036], thus, noninferiority was shown. Serious adverse events linked to rifampin where more frequent in the High-dose group (7%) than in the Low-dose group (1.6%, p=0.0043). Patients in the High-dose group were less likely to remain in the per-protocol analysis (57%, versus 67% in the Low-dose group). Noninferiority was also shown in the per-protocol analysis. Conclusion Among patients with confirmed Staphylococcus sp. bone and joint infection that were managed with standard surgical procedures, antibiotic therapy with daily 10 mg/kg of rifampin was shown to be noninferior to 20 mg/kg. Severe adverse events linked to rifampin where more frequent in the 20 mg/kg group. Disclosures Cedric Arvieux, MD, GILEAD: Advisor/Consultant|ViiV: Advisor/Consultant Florian Lemaitre, PharmD, Astellas: Grant/Research Support|Chiesi: Grant/Research Support|Pfizer: Scientific meeting fees|ViiV: Scientific meeting fees Aurélien Lorleac'h, MD, Gilead: Hospitality|GSK: Hospitality|Nestlé Home Care: Hospitality|ViiV Healthcare: Hospitality Thomas Guimard, MD, Gilead: Convention invitation|Menarini France: Hospitality|MSD: Hospitality|Pfizer: Advisor/Consultant|Shionogi BV: Hospitality Gwenael Lemoal, MD, Gilead: Hospitality|MSD: Hospitality|Viiv Heathcare: Advisor/Consultant
Current international guidelines recommend either boosted protease inhibitor (PI/r)-based or integrase inhibitors (INSTI)-based regimens during primary HIV infection (PHI), even though the latter have only demonstrated their superiority at the chronic stage. We compared the effectiveness of INSTI-based versus PI/r-based combined antiretroviral therapy (cART) initiated during PHI.This study was conducted among patients who initiated cART between 2013 and 2017, using data from the ANRS-PRIMO cohort and the Dat'AIDS study. Cumulative proportions of patients reaching viral suppression (HIV-1 RNA <50 copies/ml) were calculated using Turnbull's estimator for interval-censored data. CD4 cells and CD4/CD8 ratio increases were estimated using mixed linear models. Results were adjusted for the data source.Among the 712 study patients, 299 received an INSTI-based cART. Patients' baseline characteristics were similar between groups. Viral suppression was reached more rapidly in INSTI-treated versus PI/r-treated patients (P < 0.01), with cumulative proportions of 32 versus 6% at 4 weeks, 72 versus 31% at 12 weeks, 91 versus 78% at 24 weeks and about 95% in both groups at 48 weeks. At 4 weeks, INSTI-treated patients had gained on average 40 CD4 cells/μl (P = 0.05) over PI/r-treated ones; mean CD4 counts were similar in the two groups at 48 weeks. The CD4/CD8 ratio followed the same pattern. Results were similar when restricted to a comparison between dolutegravir-based versus darunavir-based cART.On the basis of this study and available literature, we recommend the use of INSTI-based cART for treatment initiation during PHI, as it leads to faster viral suppression and immune restoration.
To evaluate the diagnostic performance of the Vela next-generation sequencing (NGS) system in conjunction with the Sentosa SQ HIV Genotyping Assay for genotyping HIV-1. Plasma RNA was extracted and templates prepared with the Sentosa SX instrument before sequencing the HIV-1 polymerase on the Sentosa SQ301 Sequencer (PGM IonTorrent). The Vela NGS System was compared with direct sequencing and the 454 GS-FLX (Roche) and MiSeq (Illumina) systems for genotypic resistance testing on clinical samples. The Vela NGS system detected majority resistance mutations in subtype B and CRF02-AG samples at 500 copies/mL and minority variants with a sensitivity of 5% at 100 000 copies/mL. The Vela NGS system and direct sequencing identified resistance mutations with 97% concordance in 46 clinical samples. Vela identified 1/20 of the 1%–5% mutations identified by 454, 5/12 of the 5%–20% mutations and 60/61 of the >20% mutations. Vela identified 3/14 of the 1%–5% mutations identified by MiSeq, 0/2 of the 5%–20% mutations and 47/47 of the >20% mutations. The resistance mutation quantifications by Vela and 454 were concordant (bias: 2.31%), as were those by Vela and MiSeq (bias: 1.06%). The Vela NGS system provides automated nucleic acid extraction, PCR reagent distribution, library preparation and bioinformatics analysis. The analytical performance was very good when compared with direct sequencing, but was less sensitive than two other NGS platforms for detecting minority variants.
Abstract Background Up to 30% of hospitalised patients with COVID-19 require advanced respiratory support, including high-flow nasal cannulas (HFNC), non-invasive mechanical ventilation (NIV), or invasive mechanical ventilation (IMV). We aimed to describe the clinical characteristics, outcomes and risk factors for failing non-invasive respiratory support in patients treated with severe COVID-19 during the first two years of the pandemic in high-income countries (HICs) and low middle-income countries (LMICs). Methods This is a multinational, multicentre, prospective cohort study embedded in the ISARIC-WHO COVID-19 Clinical Characterisation Protocol. Patients with laboratory-confirmed SARS-CoV-2 infection who required hospital admission were recruited prospectively. Patients treated with HFNC, NIV, or IMV within the first 24 h of hospital admission were included in this study. Descriptive statistics, random forest, and logistic regression analyses were used to describe clinical characteristics and compare clinical outcomes among patients treated with the different types of advanced respiratory support. Results A total of 66,565 patients were included in this study. Overall, 82.6% of patients were treated in HIC, and 40.6% were admitted to the hospital during the first pandemic wave. During the first 24 h after hospital admission, patients in HICs were more frequently treated with HFNC (48.0%), followed by NIV (38.6%) and IMV (13.4%). In contrast, patients admitted in lower- and middle-income countries (LMICs) were less frequently treated with HFNC (16.1%) and the majority received IMV (59.1%). The failure rate of non-invasive respiratory support (i.e. HFNC or NIV) was 15.5%, of which 71.2% were from HIC and 28.8% from LMIC. The variables most strongly associated with non-invasive ventilation failure, defined as progression to IMV, were high leukocyte counts at hospital admission (OR [95%CI]; 5.86 [4.83–7.10]), treatment in an LMIC (OR [95%CI]; 2.04 [1.97–2.11]), and tachypnoea at hospital admission (OR [95%CI]; 1.16 [1.14–1.18]). Patients who failed HFNC/NIV had a higher 28-day fatality ratio (OR [95%CI]; 1.27 [1.25–1.30]). Conclusions In the present international cohort, the most frequently used advanced respiratory support was the HFNC. However, IMV was used more often in LMIC. Higher leucocyte count, tachypnoea, and treatment in LMIC were risk factors for HFNC/NIV failure. HFNC/NIV failure was related to worse clinical outcomes, such as 28-day mortality. Trial registration This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.
The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) is a global federation of clinical research networks that work collaboratively to prevent illness and deaths from infectious disease outbreaks. In 2014, we proposed that effective and timely research during outbreaks of emerging infections would benefit from pre-prepared research tools, global collaboration, and research-ready clinical networks.1 After applying this research model to several outbreaks, and particularly the COVID-19 pandemic, we can now explore what has been achieved to date.
Host factors seem to be crucial for the spontaneous clearance of hepatitis C virus (HCV). Monocytes play a pivotal role in innate immunity and help regulate adaptive responses. This study assesses the characteristics of monocytes from patients with self-limiting HCV infections. We studied 35 consecutive patients [11 with a self-limiting HCV infection, 16 chronically infected with HCV and sustained virological responders (SVR) following antiviral therapy, and eight chronically infected HCV but untreated] and eight healthy donors (HD). The production of interleukin (IL)-10, tumour necrosis factor-alpha (TNF-alpha) and IL-12p40 by monocytes stimulated with lipopolysaccharides(LPS) or HCV Core protein was measured by enzyme-linked immunoassay. Monocyte surface markers were analysed by flow cytometry. LPS and Core protein triggered IL-10 and TNF-alpha production, but monocytes from self-limiting infection patients produced significantly less IL-10 and TNF-alpha than those of SVR, chronically infected or HD (P < 0.05), while IL-12p40 production was unchanged. This cytokine production profile did not appear to be due to expansion of the CD14(+) CD16(+) monocyte subset or to a classical or alternative activation monocyte profile. Monocytes from self-limiting infection patients had more CCR7 than those from SVR or chronically infected patients (P < 0.05). Monocytes of self-limiting infection patients appear to produce little IL-10 and TNF-alpha in response to viral or unspecific stimulation and to have a higher CCR7 expression. This profile seems to be independent to a particular monocyte subset or activation state. Low IL-10 production may help establish an effective immune response and spontaneous HCV clearance.
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