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Background: The infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), the causal agent of coronavirus disease 2019 (COVID-19), is associated with coagulation abnormalities, in which endothelial injury/dysfunction may be a key pathogenic mechanism. Endothelial dysfunction triggers tissue factor (TF) expression. Activated factor VII-antithrombin (FVIIa-AT) complex is a potential biomarker of prothrombotic diathesis reflecting FVIIa-TF interaction. Aim(s): To evaluate FVIIa-AT plasma levels in subjects with COVID-19 pneumonia. Method(s): FVIIa-AT plasma levels were assessed in 40 subjects (30 males and 10 females;64.8 +/- 12.3 years) admitted for COVID-19 pneumonia during the first pandemic wave in Italy (April 2020). FVIIa-AT levels were compared with those of two sex-and age-matched groups of hospitalized subjects without COVID-19, with or without laboratory signs of systemic inflammation. The concentration of FVIIa-AT was measured by ELISA on frozen citrate plasma samples. Data of coagulant activities of factor II (FII:c), factor V (FV:c), and factor VIII (FVIII:c) were available in a subgroup of subjects. Result(s): Hospitalized COVID-19 patients had FVIIa-AT levels significantly higher than sex-and age-matched no COVID-19 subjects (Table 1), either with or without inflammation (p = 0.013 and p = 0.017 by ANOVA with Tukey post-hoc comparison, respectively). No difference in FVIIa-AT levels was observed between no COVID-19 subjects with or without inflammation (p = 0.995). The association between COVID-19 and FVIIa-AT levels in the whole study sample remained significant by linear regression analysis adjusted for sex, age, C reactive protein, estimated glomerular filtration rate, fibrinogen, prothrombin time, and activated partial thromboplastin time (B coefficient 0.322 with standard error 0135, p = 0.019). In sub-analysis COVID-19 patients showed also lower FII:c, FV:c, and FVIII:c levels (Table 1). Conclusion(s): Our results indicate that SARS-CoV2 infection, at least during the first pandemic wave, was characterized by increased FVIIa-AT levels, thereby suggesting an increased FVIIa-TF interaction, which may be consistent with increased TF expression/activation due to SARS-CoV2 -induced endotheliopathy.
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Background: The vaccination campaign against COVID-19 has a substantial beneficial public health impact, but vaccine hesitancy or issues to the access to vaccine could undermine the efforts made. We aim to determine the proportion of people living with HIV (PLWH) not vaccinated for COVID-19 in a cohort of PLWH in Italy and identify predictors of missing vaccination. Methods: Cross sectional study conducted in the Icona network. All PLWH of the centers participating the study with at least 1 follow-up in 2020-2021 were included. Their vaccination status for COVID-19 has been evaluated till 08Oct2021, before entering in the 3rd booster dose campaign for fragile populations in Italy. Data on vaccination status have been collected by medical records and/or administrative databases. Descriptive statistics, crude and adjusted logistic regression models for identifying predictors of not being vaccinated (0 doses received) were used. Results: Vaccination status has been assessed for 3,242 subjects from 17 centers of the cohort. 319/3,242 resulted still not vaccinated (9.8%) and 2,923 received at least one dose (90.2%). The full cycle has been completed by 2,732 subjects (85.5%). 89.1% of PLWH received a mRNA vaccine, 6.6% a viral vector and 4.3% unknown. Characteristics of patients according to being vaccinated or not are shown in Table 1A. In the adjusted logistic regressions, PLWH who did not receive the vaccine were more frequently younger (per 10 years younger AOR=1.22, 95%CI 1.07-1.38), and current/ex injecting drug users (IDU) (AOR=1.61, 95%CI 1.01-2.57), while having a current HIV-RNA < 50 copies mL (AOR=0.62, 95%CI 0.44-0.89), no previous diagnosis of COVID-19 (AOR=0.52, 95%CI 0.30-0.92) and being MSM (AOR=0.63, 95%CI 0.46-0.86) had lower risk to miss vaccination. Conclusion: The acceptance and uptake of vaccine among PLWH has been high, with a proportion of patients who completed the full vaccination cycle higher than targeted general population in Italy (85.5% vs 78.3% at W40-2021). Access to vaccination has been favourable for PLWH but some challenges remain for IDU/ex-IDU PLWH. The vaccination hesitancy lasts in younger population. MSMs seem to have a stronger attitude to protection, whereas patients with unsuppressed HIV-RNA could have a lower compliance reflected also in a lower COVID-19 vaccine uptake. Some selection bias on the population in analysis cannot be ruled out. These findings could help to develop interventions for increasing vaccination uptake for PLWH in future.
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Background: COVID-19 is characterized by a dysregulated inflammatory response associated with disease severity, poor prognosis and death. The aim of this study was to describe the real-life use of high-dose anakinra (ANK, a recombinant IL-1 receptor antagonist) among patients with COVID-19 who received remdesivir (REM). Methods: Cohort study including 277 patients with COVID-19 hospitalized at IRCCS San Raffaele Hospital between September 1st,2020 and February 28th, 2021;58 patients were treated with REM+ANK and 219 patients with REM only. ANK was administered intravenously at a dose of 5mg/kg every 12 hours. Patients were treated according to available local and international guidelines;corticosteroids and anticoagulation were administered when not contraindicated. Results are described by median (IQR) or frequency (%);P-values (P) were calculated by chi-square or Fishers' exact test and Wilcoxon rank-sum test, as appropriate. Survival estimates at 28 days were calculated using Kaplan-Meier curves. Results: At hospital admission (Table 1), patients treated with REM+ANK tended to be older [69 years (57-77) vs 62 years (53-75), P=0.06], had a significant lower PaO2/FiO2 [135 (91-220) vs 246 (172-299), P=0.0001], higher aspartate aminotransferase [51U/L (34-74) vs 40U/L (30-53), P=0.001], lactate dehydrogenase [405U/L (296-496) vs 334U/L (279-419), P=0.008], D-dimer [0.86mcg/mL (0.48-1.57) vs 0.67mcg/mL (0.39-1.17), P=0.048], ferritin [1167ng/mL (804-1983) vs 683ng/mL (391-1153), P<0.0001] and C-reactive protein [82mg/L (38-136) vs 58 mg/L (27-96), P=0.004), and were more frequently admitted to the Intensive Care Unit within the first 48 hours [3 (1.1%) vs 0, P=0.007). REM and ANK were started early within a median of 0 (0-2) and 1.5 days (0-3) since hospitalization, respectively. The Kaplan-Meier estimate of mortality at 28 days was 17.2% (95%CI 8.8-32.1%) in the REM+ANK group (8 deaths) and 21.4% (95%CI 13.3-33.3%) in the REM group (18 deaths;log-rank test P=0.797). Median time to death was 14 days (9-29) in the REM+ANK group vs 19 days (12-27) in the REM group (P=0.523). Conclusion: Real-life use of high-dose ANK in COVID-19 patients treated with REM was reserved for subjects with severe respiratory failure and a more pronounced inflammatory status. Nevertheless, mortality at 28 days was not significantly different among patients treated with or without ANK. Further analyses are warranted to verify the impact of ANK addition to REM in patients with a hyperinflammatory profile.
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Background. Evidence regarding the impact of remdesivir (RDV) on SARSCoV-2 viral clearance (VC) is scarce. Aim of this study was to compare VC timing in COVID-19 patients who received RDV with those who did not. Methods. Matched-cohort study conducted (25 February 2020-15 April 2021) at the IRCSS San Raffaele, Milan, Italy. The study enrolled hospitalized patients with pneumonia and a SARS-CoV-2 positive nasopharyngeal swab (NPS) at admission and at least one NPS during follow-up. Follow-up started at hospital admission and ended at the date of the first negative NPS (within 30 days after discharge). Patients who received RDV (cases) and patients who did not (controls) were matched based on age (±5 years), sex and PaO2/FiO2 (P/F;±10 mmHg) values at admission. NPS were analyzed with RT-PCR. Results described as median (IQR) or frequency (%). Time to VC was estimated with Kaplan-Meier curve and compared with log-rank test. Results. 648 patients were enrolled: 216 cases and 432 controls. Patients' characteristics at admission are reported in Table 1. VC was observed in 490 patients (75.6%) in a median time of 25 (16-34) days. Overall, time to VC was similar in patients receiving or not receiving remdesivir (p=0.519). However, time to VC was different when considering both the use of RDV (yes vs no) and age (≤ or > 63 years), as shown in Figure 1A. A significant finding was also observed considering the use of RDV and P/F values at admission (≤ or > 200 mmHg), as reported in Figure 1B. Among the 490 patients who reached VC during follow-up, overall time to VC was similar in patients receiving or not receiving RDV (p=0.075;Figure 2A);however, RDV use was associated with a higher probability of VC in the subgroup of patients with P/F admission values ≤ 200mmHg (p=0.035;Figure 2B), in the age group 55-65 years (p=0.025;Figure 2C) and in patients with comorbidities (p=0.028). Time to viral clearance among the 490 patients who reached VC during follow-up. Panel A: time to VC according to RDV use. Panel B: time to VC according to RDV and P/F ratio value at admission. Panel C: time to VC according to RDV in the age group 55-65 years. Conclusion. Time to viral clearance was similar in patients receiving or not receiving remdesivir;however the use of RDV was associated with a benefit on time to viral clearance in younger patients and in those with a P/F ratio at admission ≤200 mmHg.
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Neutralizing monoclonal antibody therapies against the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) play a significant role both in the prevention and treatment of the coronavirus disease 2019 (COVID-19). In this review we discuss the monoclonal antibody therapies that have received preliminary authorization for use in COVID-19 patients by the U.S. Food and Drug Administration or the European Medicines Agency. We review here their mechanisms of action, their efficacy in prophylaxis and treatment, their indications for use, and the impact of SARS-CoV-2 variants of concern on their activity.
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Background : COVID-19 (Coronavirus Disease 2019) is associated with High rates of thrombosis in hospitalized patients leading to varying pharmacologic thromboprophylaxis use based on rapidly changing societal guidance, institutional protocols from local expertise, and geographic patterns of practice. Aims : To assess the efficacy and safety of enoxaparin in hospitalized patients with moderate to severe COVID-19 infection. Methods : Phase II single-arm interventional prospective study including all patients treated with the study drug and an observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study. Each patient was followed-up for a minimum of 90 days after COVID19 diagnosis. Patients included in the interventional study received subcutaneous enoxaparin in a single daily dose of:60 mg once daily in case of body weight of 45 to 60 kg 80 mg per day in case of weight from 61 to 100 kg or 100 mg once daily in case of bodyweight >100 kg for 14 days, with dose adjustments on the basis of anti-factor Xa activity monitoring. Patients included in the observational cohort received standard thrombo-prophylaxis with subcutaneous enoxaparin 40 mg/die. Primary outcomes were all-cause in-hospital 30-day and 90 mortality rates. Secondary outcomes were the proportion of patients in the severe or critical stage of disease at the end of treatment, proportion of patients who developed major and non-major bleeding events and thromboembolic complications, time to first negative RT-PCR on nasofaringeal swab, reduction of viral load in blood. Results : Recruitment of 100 patients enrolled phase II single-arm interventional prospective study has been completed, while the recruitment of 200 patients in the observational prospective cohort study is ongoing. Conclusions : Full results will be available by June 2021.
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Background: Remdesivir (RDV), a direct-acting nucleotide pro-drug inhibitor of viral RNA-dependent RNA polymerases, was approved by the FDA for the treatment of hospitalized patients (pts) with COVID-19 infection and has been shown to shorten time to recovery and improve clinical outcomes in randomized clinical trials. We present the final Day 28 (D28) analysis of RDV vs standard of care (SOC) (interim Day 14 [D14] analysis published [Olender et al. Clin Infect Dis 2020]). Methods: Final comparative analysis from two studies: a prospective phase 3, randomized study of RDV (RDV cohort) and a real-world retrospective cohort study of SOC (non-RDV cohort). Both studies enrolled pts with SARS-CoV-2 infection confirmed by polymerase chain reaction, who had oxygen saturation ≤94% on room air or required supplemental oxygen and had pulmonary infiltrates. Pts in the RDV cohort were randomized 1:1 to receive IV RDV for 5 or 10 days (200 mg on Day 1 followed by 100 mg/day on Days 2-5 or 2-10), plus SOC;the two randomized dose-groups were combined for analysis. Pts in the non-RDV cohort received SOC as determined by local treatment practices (excluding RDV). Analysis populations were balanced using propensity score (PS) matching. The coprimary endpoints were D14 clinical recovery (determined using a 7-point ordinal scale) and D28 all-cause mortality. Factors associated with D28 mortality were assessed using a multivariable logistic regression model. Results: After PS matching, baseline characteristics were generally similar in the RDV and non-RDV cohorts;median age 61 years, 63% male, 42% obese, 12% Black, 71% no/low-flow oxygen use, 25% high-flow oxygen, 3% ventilated. Pts in the RDV cohort had significantly higher D14 clinical recovery rates (65% vs 57%) and significantly lower D28 mortality rates (12% vs 16%) compared with the non-RDV cohort (Table). In the multivariable analysis, in addition to RDV use, a lower risk of death at D28 was associated with: younger age;being female;being White (versus being Black/African American);receiving an HIV protease inhibitor prior to baseline;not having cardiovascular disease or COPD;more days of symptoms prior to baseline;and being on room air or low-flow oxygen at baseline (versus being on invasive mechanical ventilation). Conclusion: RDV was associated with significantly higher rates of clinical recovery at Day 14 and lower Day 28 mortality compared with SOC in hospitalized pts with severe SARS-CoV-2 infection.
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Background: Remdesivir (RDV), an RNA-dependent RNA polymerase inhibitor of SARS-CoV-2, and its intravenous formulation excipient, cyclodextrin, are renally cleared. We sought to characterize whether RDV was associated with worsening renal function in hospitalized patients with moderate COVID-19. Methods: We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, oxygen saturation >94% on room air and eGFR ≥50 mL/ min/1.73m2. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone. Also included in this analysis were patients who enrolled in an extension phase of the trial, receiving 10d of RDV. RDV was dosed intravenously at 200 mg on d1 and 100 mg daily thereafter. Acute kidney injury (AKI) was defined as an increase in serum creatinine from baseline and classified as Stage 1 (increase > 0.3 and % change ≤25%, or % change >25% and ≤ 100%), Stage 2 (% change >100% and ≤200%), Stage 3 (% change >200%). For AKI development (ever/never for stage 1 or greater), age-adjusted risk ratios (RR) and 95% Wald confidence intervals (CI) were reported. Results: 1005 patients (822 [83%] RDV, 183 [17%] SoC) with creatinine values collected through d14 were evaluated. Baseline patient demographics, creatinine, and eGFR were mostly similar between RDV vs SoC arms. Worsening renal function was observed less frequently in patients receiving RDV vs SOC (7% vs 10%, p=0.03, Table). After adjustment for age, there was no significant association of RDV with risk of AKI relative to SoC (RR=0.66;95% CI 0.40, 1.09). Most AKI events were observed in patients with baseline eGFR >90 mL/min, with few events occurring in patients with a baseline eGFR 50-59 mL/min. In patients who developed Stage 3 AKI, those treated with RDV (n=2, 0.2%) returned to baseline creatinine values while those on SOC (n=4, 2%) remained elevated to d14. No difference in AKI between treatment arms was observed in patients with a history of chronic kidney disease (CKD;RDV: n=6 [12%] vs SOC: n=2 [40%] p=0.14). Older age, history of CKD, and eGFR status at baseline were independently associated with worsening renal function. Conclusion: AKI events were observed less frequently in patients with moderately severe COVID-19 patients treated with RDV compared to SoC.
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Background: It has been observed that lockdown restrictions during COVID-19 pandemic may have had a negative impact on HIV epidemic goals with disruption in care. We aim to analyse the trends in non-viral suppression for PLWH during and after the lockdown for COVID-19 pandemic in Italy compared to 2019. Methods: We included all participants in the ICONA cohort for whom there was ≥1 viral load (VL) in the window Nov 2019-Jan 2020 and with most recent VL≤50 copies/mL (exposed to lockdown), and over Nov 2018-Jan 2019 (not exposed). New enrolments in the study period were excluded. At population level and separately by year, we calculated proportion with VL≤50 copies/mL at each month over March-September and we performed an intermittent time series (ARIMA) model centred in March. In addition, we defined an individual outcome using the first VL over May-September (>50 vs. ≤50 copies/mL), comparing proportion with VL>50 copies/mL between exposed and not exposed by means of logistic regression models. PLWH with missing VL in the outcome window were excluded from the analysis. We also performed an alternative analysis in which censoring bias was minimised using inverse probability of weighting. Sensitivity analyses were performed after restricting to clinical sites with electronic linkage with laboratory data and to the subset of PLWH under follow-up in both years. Results: A total of 3,684 PLWH were included (2019=2,948;2020=736). PLWH exposed to lockdown were significantly older, less frequently MSM, non-Italian, had a higher CD4+ count and more frequently resident in north of Italy. The mean proportion of VL<50 copies/mL was 97% at March 2020 (ref.), 99% before March 2020, 82% at April 2020 (ARIMA estimates -21% 95% CI:-28%;-14%;P=0.01) and 97% after April 2020. In the 2019, the same proportions were 100%, 98%, 95%, and 97% with evidence for a lower drop in April (-6%, 95% CI:-8%;-3%, p=0.02). The results of the logistic regression model are reported in Table 1. When restricting to sites with electronic VL linkage and to those followed-up in both years the IPW OR of 2020 vs. 2019 were 1.23 (0.69-2.18) and 1.03 (0.48-2.19), respectively. Conclusion: We found little evidence for a difference in the proportion of PLWH with a VL>50 copies/mL, following stable suppression, in the period post lockdown due to COVID-19 as compared to the previous year. Although selection bias was minimized, reasons for a missing VL should be further investigated.
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Background: Remdesivir (RDV) has been shown to shorten recovery time and was well tolerated in patients with severe COVID-19. Here we report baseline characteristics associated with clinical improvement at day (d) 14. Methods: We enrolled hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation >94% on room air, and radiological evidence of pneumonia. Patients were randomized 1:1:1 to receive 5d or 10d of intravenous RDV once daily plus standard of care (SoC), or SoC only. For this analysis, patients were followed through discharge, d14, or death. Baseline demographic and disease characteristics associated with clinical improvement in oxygen support (≥2-point improvement on a 7-category ordinal scale ranging from discharge to death) were evaluated using multivariable logistic regression methods. Results: 584 patients were randomized and treated (5/10d RDV, n=384;SoC: n=200). 159 (27%) were ≥65y, 227 (39%) female, 328 (61%) white, 102 (19%) Asian, and 99 (19%) Black. 252 participants (43%) were enrolled in Europe, 260 (45%) North America (NA), and 72 (12%) in Asia. Most patients (483 [83%]) were not on supplemental oxygen but required medical care at baseline. In a multivariable model, 5/10d RDV was significantly positively associated with clinical improvement (adjusted odds ratio [OR] 1.69, 95% CI: 1.08, 2.65;p=0.0226). Significant covariables positively associated with clinical improvement included age < 65y (p< 0.0001) and region of treatment (Europe and NA vs Asia, p< 0.0001 each;Table);other examined factors were not significantly associated with clinical improvement, including gender, race, ethnicity, baseline oxygen support, duration of symptoms and hospitalization, obesity, and baseline transaminase levels. Conclusion: In moderate COVID-19 patients, after adjusting for treatment arm, age < 65y and region (NA vs Asia;Europe vs Asia) were associated with higher rates of clinical improvement. These observations recapitulate younger age as positive prognostic factor, and highlight the differences in the impact of the pandemic globally.
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At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak spread from China all around the world, causing thousands of deaths. In Italy, the hardest hit region was Lombardy, with the first reported case on 20 February 2020. San Raffaele Scientific Institute - a large tertiary hospital and research centre in Milan, Italy - was immediately involved in the management of the public health emergency. Since the beginning of the outbreak, the elective surgical activity of the hospital was rapidly reduced and large areas of the hospital were simultaneously reorganised to admit and assist patients with coronavirus disease 2019 (COVID-19). In addition, the hospital became the regional referral hub for cardiovascular emergencies in order to keep ensuring a high level of health care to non-COVID-19 patients in northern Italy. In a few days, a COVID-19 emergency department was created, improving the general ward capacity to a total number of 279 beds dedicated to patients with COVID-19. Moreover, the number of intensive care unit (ICU) beds was increased from 28 to 72 (54 of them dedicated to patients with COVID-19, and 18 to cardiology and cardiac surgery hub emergencies), both converting pre-existing areas and creating new high technology spaces. All the involved health care personnel were rapidly trained to use personal protection equipment and to manage this particular category of patients both in general wards and ICUs. Furthermore, besides clinical activities, continuously important research projects were carried out in order to find new strategies and more effective therapies to better face an unprecedented health emergency in Italy.
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The aim of this study was to evaluate the impact of early treatment with corticosteroids on SARS-CoV-2 clearance in hospitalized COVID-19 patients. Retrospective analysis on patients admitted to the San Raffaele Hospital (Milan, Italy) with moderate/severe COVID-19 and availability of at least two nasopharyngeal swabs. The primary outcome was the time to nasopharyngeal swab negativization. A multivariable Cox model was fitted to determine factors associated with nasopharyngeal swab negativization. Of 280 patients included, 59 (21.1%) patients were treated with steroids. Differences observed between steroid users and non-users included the proportion of patients with a baseline PaO2/FiO2 ≤ 200 mmHg (45.8% vs 34.4% in steroids and non-steroids users, respectively; p = 0.023) or ≤ 100 mmHg (16.9% vs 12.7%; p = 0.027), and length of hospitalization (20 vs 14 days; p < 0.001). Time to negativization of nasopharyngeal swabs was similar in steroid and non-steroid users (p = 0.985). According to multivariate analysis, SARS-CoV-2 clearance was associated with age ≤ 70 years, a shorter duration of symptoms at admission, a baseline PaO2/FiO2 > 200 mmHg, and a lymphocyte count at admission > 1.0 × 109/L. SARS-CoV-2 clearance was not associated with corticosteroid use. Our study shows that delayed SARS-CoV-2 clearance in moderate/severe COVID-19 is associated with older age and a more severe disease, but not with an early use of corticosteroids.