Antibiotic Consumption 2017-2022 in 30 Private Hospitals in France: Impact of Antimicrobial Stewardship Tools and COVID-19 Pandemic.

Our aim was to determine the impact of antimicrobial stewardship tools (ASTs) and the COVID-19 pandemic on antibiotic consumption (AC). We used the national software Consores® to determine AC in DDD/1000 days of hospitalization from 2017 to 2022 in voluntary private hospitals in France. The ASTs considered were: 1. internal guidelines; 2. the list of antibiotics with restricted access; 3. the presence of an antibiotic referent or 4. an ID specialist; and 5. proof of an annual meeting on antimicrobial resistance. Institutions with dedicated units for COVID-19 patients were specified. In 30 institutions, the total AC varied from (means) 390 to 405 DDD/1000 DH from 2017 to 2022. Fluoroquinolones and amoxicillin/clavulanate consumption decreased from 50 to 36 (p = 0.003) and from 112 to 77 (p = 0.025), respectively, but consumption of piperacillin/tazobactam increased from 9 to 21 (p < 0.001). Over the study period, 10 institutions with ≤2 AST had lower AC compared to 20 institutions with ≥3 AST (p < 0.01). COVID-19 units opened in 10 institutions were associated with a trend toward higher macrolide consumption from 15 to 25 from 2017 to 2020 (p = 0.065) and with an acceleration of piperacillin/tazobactam consumption from 2020 to 2022 (p ≤ 0.003). Antibiotic consumption in 30 private hospitals in France was inversely related to the number of AST. The COVID-19 pandemic was associated with limited impact on AC, but special attention should be paid to piperacillin/tazobactam consumption.

Prosthetic joint infections: 6 weeks of oral antibiotics results in a low failure rate.

BACKGROUND: Need for parenteral administration and total duration of antibiotic therapy for prosthetic joint infection (PJI) are debated. We report our PJI management, in which outpatient care is privileged. METHODS: This was a retrospective multicentre cohort study of PJI managed from January 2017 to Jun 2021. Microbial diagnosis was based on surgical samples. Surgical procedures and antibiotic treatments were reported. Chronic PJI was defined by a course >1 month. Oral antibiotic therapy (OAT) was defined by exclusive use of oral antibiotics or by ≤3 days of parenteral treatments. Management failure was defined by clinical and/or microbial relapse of PJI over 24 months after surgical treatment. RESULTS: One hundred and seventy-two patients from 13 institutions were included: 103 were male (60%) and mean age was (±SD): 73 ±â€Š12 years. Sites for PJI were mainly hip (50%) and knee (35%), being chronic infections in 70 cases (41%). The main bacterial genus in monomicrobial infections was Staphylococcus spp. (60%). We recorded 41 (24%) implant exchanges. An OAT was prescribed in 76 cases (44%), and the median (range) course for parenteral route was 6 days (4-180) for 96 cases. Median (range) duration of antimicrobials was 42 days (21-180). Management failure was observed in 7/76 (9.2%) cases treated with OAT and 15/96 (15.6%) treated with prolonged parenteral therapy. In multivariate analysis, risk factors for failure were a knee PJI [adjusted OR (95% CI) = 3.27 (1.27-8.40)] and a polymicrobial infection [4.09 (1.46-11.49)]. CONCLUSIONS: OAT for 6 weeks for PJI was associated with a low rate of management failure.

CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.

Background: CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers. Methods: We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays. Results: CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels, which were associated with proliferative activity. Absence of CDK4 phosphorylation in cell lines was associated with CDK4/6i insensitivity. RB1 defects (the primary cause of intrinsic CDK4/6i resistance) were not found in 5/7 tumors without detectable phosphorylated CDK4. A previously developed 11-gene expression signature identified the likely unresponsive tumors, lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib by completely and permanently arresting proliferation. These combinations prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Conclusion: Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.

Diagnostic uncertainty in infectious diseases: Advocacy for a nosological framework.

Diagnostic uncertainty (DU) is frequent in infectious diseases (ID), being recorded in 10% to over 50% of patients. Herein, we show that in several fields of clinical practice, high rates of DU are constant over time. DUs are not taken into account in guidelines, as therapeutic propositions are based on an established diagnosis. Moreover, while other guidelines underline the need for rapid broad-spectrum antibiotic therapy for patients with sepsis, many clinical conditions mimic sepsis and lead to unnecessary antibiotic therapy. Considering DU, many studies have been carried out to look for relevant biomarkers of infections, which also attest to non-infectious diseases mimicking infections. Therefore, diagnosis is often primarily a hypothesis, and empirical antibiotic therapy should be reassessed when microbiological data are available. However, other than for urinary tract infections or unexpected primary bacteremia, the high frequency of sterile microbiological samples implies that DU remains central in follow-up, which does not facilitate clinical management or antibiotic optimization. The main way to resolve the therapeutic challenge of DU could be to precisely describe the latter through a consensual definition that would facilitate consideration of DU and its mandatory therapeutic implications. A consensual definition of DU would also clarify responsibility and accountability for physicians in the antimicrobial approval process and l provide an opportunity to instruct their students in this large field of medical practices and to productively conduct relevant research.

Simplified antibiotic guidelines in urology are associated with decreased multidrug-resistant Enterobacterales.

PURPOSE: A simplified therapeutic guideline (STG) was established in our urology ward in 2019 for urinary infections. Our aim was to describe the level of physician adherence to STG and the impact of a limited number of antibiotic compounds on the rate of multidrug-resistant (MDR) bacteria. As guidelines should improve patient care, unfavorable outcomes were also reported. METHODS: The STG for community-acquired and nosocomial urinary infections, including six antibiotics, was established in November 2019 and has been officially applied since January 2020. Treatment duration has to be ≤14 days. We conducted a before-after study to measure physician adherence to the STG for bacteremia treatment between January 2017 and December 2022. Adherence was defined as exclusive use of STG antibiotics. All isolated bacteria from blood cultures were recorded, including MDR Enterobacterales, defined as AmpC ß-lactamase- or ESBL-producing strains. Unfavorable outcomes were defined as uncontrolled infection, a second surgical procedure, ICU requirement, and/or death. RESULTS: Seventy-six cases of bacteremia occurred between January 2017 and December 2019, and ninety between January 2020 and December 2022. The main comorbid condition was urological cancer (46%). The main reason for surgery was ureteral stent (32%). Antibiotic management in accordance with STG increased from 18% to 52%, p < 0.001, and treatments > 14 days decreased from 53% to 28%, p < 0.001. MDR Enterobacterales bacteremia was reduced from 52% to 35%, p = 0.027. The rate of unfavorable outcomes was unchanged. CONCLUSION: STG adherence in urology was satisfactory and associated with reduced MDR Enterobacterales bacteremia.

CDK4/6 Inhibitors in Pancreatobiliary Cancers: Opportunities and Challenges.

Existing treatment strategies for pancreatobiliary malignancies are limited. Nowadays, surgery is the only path to cure these types of cancer, but only a small number of patients present with resectable tumors at the time of diagnosis. The notoriously poor prognosis, lack of diverse treatment options associated with pancreaticobiliary cancers, and their resistance to current therapies reflect the urge for the development of novel therapeutic targets. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as an attractive therapeutic strategy in a number of cancers since their approval for treatment in patients with ER+/HER- breast cancer in combination with antiestrogens. In this article, we discuss the therapeutic potential of CDK4/6 inhibitors in pancreatobiliary cancers, notably cholangiocarcinoma and pancreatic ductal adenocarcinoma.

Prevalence of post-acute coronavirus disease 2019 symptoms twelve months after hospitalization in participants retained in follow-up: analyses stratified by gender from a large prospective cohort.

OBJECTIVES: Persistent post-acute coronavirus disease 2019 (COVID-19) symptoms (PACSs) have been reported up to 6 months after hospital discharge. Herein we assessed the symptoms that persisted 12 months (M12) after admission for COVID-19 in the longitudinal prospective national French coronavirus disease cohort. METHODS: Hospitalized patients with a confirmed virological diagnosis of COVID-19 were enrolled. Follow-up was planned until M12 after admission. Associations between persistence of ≥3 PACSs at M12 and clinical characteristics at admission were assessed through logistic regression according to gender. RESULTS: We focused on participants enrolled between 24 January 2020 and 15 July 2020, to allow M12 follow-up. The M12 data were available for 737 participants. Median age was 61 years, 475 (64%) were men and 242/647 (37%) were admitted to intensive care units during the acute phase. At M12, 27% (194/710) of the participants had ≥3 persistent PACS, mostly fatigue, dyspnoea and joint pain. Among those who had a professional occupation before the acute phase, 91 out of 339 (27%) were still on sick leave at M12. Presence of ≥3 persistent PACS was associated with female gender, both anxiety and depression, impaired health-related quality of life and Medical Muscle Research Council Scale <57. Compared with men, women more often reported presence of ≥3 persistent PACSs (98/253, 39% vs. 96/457, 21%), depression and anxiety (18/152, 12% vs. 17/268, 6% and 33/156, 21% vs. 26/264, 10%, respectively), impaired physical health-related quality of life (76/141, 54% vs. 120/261, 46%). Women had less often returned to work than men (77/116, 66% vs. 171/223, 77%). CONCLUSIONS: One fourth of the individuals admitted to hospital for COVID-19 still had ≥3 persistent PACSs at M12 post-discharge. Women reported more often ≥3 persistent PACSs, suffered more from anxiety and depression and had less often returned to work than men.

An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4.

Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. By identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

Platelet caspase-1 and Bruton tyrosine kinase activation in patients with COVID-19 is associated with disease severity and reversed in vitro by ibrutinib.

Background: Severity of coronavirus disease 2019 (COVID-19) is often associated with thrombotic complications and cytokine storm leading to intensive are unit (ICU) admission. Platelets are known to be responsible for abnormal hemostasis parameters (thrombocytopenia, raised D-dimers, and prolonged prothrombin time) in other viral infections through the activation of the nucleotide-binding domain leucine repeat rich containing protein 3 inflammasome induced by signaling pathways driven by Bruton tyrosine kinase (BTK) and leading to caspase-1 activation. Objectives: We hypothesized that caspase-1 activation and the phosphorylation of BTK could be associated with the severity of the disease and that ibrutinib, a BTK inhibitor, could inhibit platelet activation. Methods and Results: We studied caspase-1 activation by flow cytometry and the phosphorylation of BTK by Western blot in a cohort of 51 Afro-Carribean patients with COVID-19 disease (19 not treated in ICU and 32 treated in ICU). Patients with a platelet count of 286.7 × 109/L (69-642 × 109/L) were treated by steroids and heparin preventive anticoagulation. Caspase-1 and BTK activation were associated with the severity of the disease and with the procoagulant state of the patients. Furthermore, we showed in vitro that the plasma of ICU patients with COVID-19 was able to increase CD62P expression and caspase-1 activity of healthy platelets and that ibrutinib could prevent it. Conclusions: Our results show that caspase-1 and BTK activation are related to disease severity and suggest the therapeutic hope raised by ibrutinib in the treatment of COVID-19 by reducing the procoagulant state of the patients.

Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of pleural mesotheliomas to CDK4/6 inhibition.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumours from short-survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.

Limited Transmission of Klebsiella pneumoniae among Humans, Animals, and the Environment in a Caribbean Island, Guadeloupe (French West Indies).

Guadeloupe (French West Indies), a Caribbean island, is an ideal place to study the reservoirs of the Klebsiella pneumoniae species complex (KpSC) and identify the routes of transmission between human and nonhuman sources due to its insularity, small population size, and small area. Here, we report an analysis of 590 biological samples, 546 KpSC isolates, and 331 genome sequences collected between January 2018 and May 2019. The KpSC appears to be common whatever the source. Extended-spectrum-ß-lactamase (ESBL)-producing isolates (21.4%) belonged to K. pneumoniae sensu stricto (phylogroup Kp1), and all but one were recovered from the hospital setting. The distribution of species and phylogroups across the different niches was clearly nonrandom, with a distinct separation of Kp1 and Klebsiella variicola (Kp3). The most frequent sequence types (STs) (≥5 isolates) were previously recognized as high-risk multidrug-resistant (MDR) clones, namely, ST17, ST307, ST11, ST147, ST152, and ST45. Only 8 out of the 63 STs (12.7%) associated with human isolates were also found in nonhuman sources. A total of 22 KpSC isolates were defined as hypervirulent: 15 associated with human infections (9.8% of all human isolates), 4 (8.9%) associated with dogs, and 3 (15%) associated with pigs. Most of the human isolates (33.3%) belonged to the globally successful sublineage CG23-I. ST86 was the only clone shared by a human and a nonhuman (dog) source. Our work shows the limited transmission of KpSC isolates between human and nonhuman sources and points to the hospital setting as a cornerstone of the spread of MDR clones and antibiotic resistance genes. IMPORTANCE In this study, we characterized the presence and genomic features of isolates of the Klebsiella pneumoniae species complex (KpSC) from human and nonhuman sources in Guadeloupe (French West Indies) in order to identify the reservoirs and routes of transmission. This is the first study in an island environment, an ideal setting that limits the contribution of external imports. Our data showed the limited transmission of KpSC isolates between the different compartments. In contrast, we identified the hospital setting as the epicenter of antibiotic resistance due to the nosocomial spread of successful multidrug-resistant (MDR) K. pneumoniae clones and antibiotic resistance genes. Ecological barriers and/or limited exposure may restrict spread from the hospital setting to other reservoirs and vice versa. These results highlight the need for control strategies focused on health care centers, using genomic surveillance to limit the spread, particularly of high-risk clones, of this important group of MDR pathogens.

Sickle cell disease patients with COVID-19 in Guadeloupe: Surprisingly favorable outcomes.

We investigate risk factors for hospitalization and difference between sickle cell syndromes in a cohort of COVID-19 sickle cell disease (SCD) adult patients managed in the Reference Center of Guadeloupe. We retrospectively collected data of symptomatic SCD adult patients infected with SARS-CoV-2 between March and December 2020. Thirty-eight SCD adult patients with symptomatic COVID-19 infection were included during the first wave, representing 9.6% of the active patient file at our center. The median age (IQR) was 39 years (24-47). Four patients were obese and two had moderate renal failure. The median duration of symptoms (IQR) was 10 days (5-15). Seventeen (44.7%) patients were hospitalized, including two in intensive care unit (ICU) for acute chest syndrome. An 85-year-old SC patient with prostate cancer died. No difference was detected between inpatient and outpatient groups in terms of age, gender, BMI, SCD clinical complications, and in history SCD treatment. There was no difference for severity, hospitalization, length of stay, ICU stay, or death between SS or Sß°-thal patients and SC or Sß+-thal patients. These overall favorable outcomes among symptomatic patients may be related to the low prevalence of comorbidity known to be linked to the more severe forms of COVID-19, but also to the prompt coordinated management of SCD patients in the Reference Center.

Dedicated team to ambulatory care for patients with COVID-19 requiring oxygen: Low rate of hospital readmission.

OBJECTIVES: We aimed to determine the impact of a dedicated medical team (DMT) on ambulatory care for patients requiring oxygen. METHODS: The DMT selected patients requiring oxygen for less than 5 l/min in the emergency department (ED). The rate of ED readmission was compared in patients managed by the DMT and those managed by the ED physicians (EDPs). Consensual treatment for COVID-19 pneumonia with oxygen requirement was steroids + preventive anticoagulation. RESULTS: A total of 1397 patients with COVID-19 came to our ED from the first to the 31st of August, 2021, among whom 580 (41%) had ambulatory care. A total of 82 (14.1%) patients were managed by the DMT, with a rate of ED readmission of 4.8% (4/82), compared with 13.6% (68/498) for those managed by EDPs (P <0.001). Focusing on the 45/498 (9.0%) patients requiring oxygen and managed by EDPs, the rate of ED readmission was 20%, P = 0.017. Prescription of the consensual treatment concerned 96% versus 40% for those patients requiring oxygen for the DMT and the EDP, respectively (P <0.001). CONCLUSION: A DMT for ambulatory care of patients with COVID-19 requiring oxygen was associated with less return to the ED than usual practices.

Real-world effectiveness of casirivimab plus indevimab in a dedicated ambulatory unit created for patients with early COVID-19 during a massive delta variant wave.

Only limited real-life data are available on the effects of neutralizing monoclonal antibodies in high-risk patients who have early COVID-19 and do not require supplemental oxygen. We prospectively studied 217 patients infected by the delta variant who received casirivimab plus indevimab in a dedicated ambulatory unit created during our 4th COVID wave. Mean age was 64 years, 94% had at least one comorbidity, and mean duration of symptoms was 2.9 days. Oxygen requirement, hospitalization, and mortality rates were 10, 6, and 2.8%, respectively. These results suggest benefits of early administration of neutralizing antibodies in high-risk patients infected with the delta variant.

Use of Antibiotic Prophylaxis for Polymicrobial Urine Culture before Urological Surgery: A Pilot Study.

INTRODUCTION: Preoperative polymicrobial urine cultures are common, but the associated risk of nosocomial infection is currently unknown. We aimed to analyze the risk of postoperative infection in patients with preoperative polymicrobial urine cultures. METHODS: This was a prospective cohort study conducted from November 2018 to October 2020. Polymicrobial urine cultures were defined by at least the presence of 3 bacteria without leukocyturia threshold on two consecutive samples in the month preceding the surgical procedure. Data on postoperative infections were collected during hospitalization until day 30. A postoperative infection was defined by the occurrence of clinical signs (fever, chills, and suppurated process on the surgical site) associated with the prescription of an antibiotic therapy. RESULTS: Sixty-eight patients were included, and seven developed a postoperative infection with a microbe identified in blood or urine cultures. There was a significant association between leukocyturia ≥104 (p = 0.02) and the administration of intraoperative antibiotic prophylaxis (p < 0.001). In contrast, there was no significant association between postoperative infections for patients with polymicrobial preoperative urine cultures and having received or not an empirical antibiotic therapy. CONCLUSION: The rate of postoperative infection in patients with polymicrobial urine culture before urological procedure was 10.2%. Further studies are needed to assess the antibiotic prophylaxis to be used in this situation.

Raltegravir Inclusion Decreases CD4 T-Cells Intra-Cellular Viral Load and Increases CD4 and CD28 Positive T-Cells in Selected HIV Patients.

Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of RLT inclusion on total intra-cellular viral DNA (TID) in cellular subsets and immune effects in patients with newly acquired undetectable plasmatic viral load (UVL). Six patients having UVL using an antiretroviral combination for 6 months and CD4 T-cells > 350/mL and <500/mL were selected to receive RLT for 3 months from M0 to M3. Patients had 7 sequential viro-immunological determinations from M-1 to M5. Immune phenotypes were determined by flow cytometry and TID quantification was performed using PCR assay on purified cells. TID (median values) at the initiation of RLT in CD4 T-cells was 117 copies/millions of cells, decreased to 27.5 on M3, and remained thereafter permanently under the cut-off (<10 copies/millions of cells) in 4 out of 6 patients. This was associated with an increase of CD4 and CD4 + CD28+ T-cells and a decrease of HLA-DR expression and apoptosis of CD4 T-cells. RLT inclusion led to decreases in the viral load along with positive immune reconstitution, mainly for CD4 T-cells in HIV patients.

Plasma microparticles of intubated COVID-19 patients cause endothelial cell death, neutrophil adhesion and netosis, in a phosphatidylserine-dependent manner.

COVID-19 has compelled scientists to better describe its pathophysiology to find new therapeutic approaches. While risk factors, such as older age, obesity, and diabetes mellitus, suggest a central role of endothelial cells (ECs), autopsies have revealed clots in the pulmonary microvasculature that are rich in neutrophils and DNA traps produced by these cells, called neutrophil extracellular traps (NETs.) Submicron extracellular vesicles, called microparticles (MPs), are described in several diseases as being involved in pro-inflammatory pathways. Therefore, in this study, we analyzed three patient groups: one for which intubation was not necessary, an intubated group, and one group after extubation. In the most severe group, the intubated group, platelet-derived MPs and endothelial cell (EC)-derived MPs exhibited increased concentration and size, when compared to uninfected controls. MPs of intubated COVID-19 patients triggered EC death and overexpression of two adhesion molecules: P-selectin and vascular cell adhesion molecule-1 (VCAM-1). Strikingly, neutrophil adhesion and NET production were increased following incubation with these ECs. Importantly, we also found that preincubation of these COVID-19 MPs with the phosphatidylserine capping endogenous protein, annexin A5, abolished cytotoxicity, P-selectin and VCAM-1 induction, all like increases in neutrophil adhesion and NET release. Taken together, our results reveal that MPs play a key role in COVID-19 pathophysiology and point to a potential therapeutic: annexin A5.