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Abstract Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven lymphoproliferative disease that usually arises in the context of reduced immunological surveillance. Based on histology, two forms of the disease are recognized, namely low-grade and high-grade LYG. Clinically, LYG universally involves the lungs and, frequently, also the skin, central nervous system, liver, and kidneys. Here, we present the case of a 55-year-old woman with a difficult-to-diagnose low-grade LYG with symptomatic lung involvement, who concomitantly was newly diagnosed with human immunodeficiency virus (HIV) infection. Rapid immune recovery achieved through antiretroviral therapy led to a complete and sustained clinical and radiological remission of LYG.

Abstract Background Long-COVID symptoms remain incompletely defined due to a large heterogeneity in the populations studied, case definitions, and settings of care. The aim of this study was to assess, in patients accessing care for Long-COVID, the profile of symptoms reported, the possible clustering of symptoms and cases, the functional status compared to pre-infection, and the impact on working activity. Methods Multicentre cohort study with a collection of both retrospective and prospective data. Demographics, comorbidities, severity and timing of acute COVID, subjective functional status, working activity and presence of 30 different symptoms were collected using a shortened version of the WHO Post COVID-19 Case Report Form. The impact on working activity was assessed in multivariable logistic regression models. Clustering of symptoms was analysed by hierarchical clustering and the clustering of cases by two-step automatic clustering. Results The study evaluated 1297 individuals (51.5% women) from 30 clinical centres. Men and women had different profiles in terms of comorbidities, vaccination status, severity and timing of acute SARS-CoV-2 infection. Fatigue (55.9%) and dyspnea (47.2%) were the most frequent symptoms. Women reported more symptoms (3.6 vs. 3.1, p

IntroductionT cells are involved in the early identification and clearance of viral infections and also support the development of antibodies by B cells. This central role for T cells makes them a desirable target for assessing the immune response to SARS-CoV-2 infection.MethodsHere, we combined two high-throughput immune profiling methods to create a quantitative picture of the T-cell response to SARS-CoV-2. First, at the individual level, we deeply characterized 3 acutely infected and 58 recovered COVID-19 subjects by experimentally mapping their CD8 T-cell response through antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I presented viral peptides. Then, at the population level, we performed T-cell repertoire sequencing on 1,815 samples (from 1,521 COVID-19 subjects) as well as 3,500 controls to identify shared “public” T-cell receptors (TCRs) associated with SARS-CoV-2 infection from both CD8 and CD4 T cells.ResultsCollectively, our data reveal that CD8 T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the T-cell response to SARS-CoV-2 peaks about one to two weeks after infection and is detectable for at least several months after recovery. As an application of these data, we trained a classifier to diagnose SARS-CoV-2 infection based solely on TCR sequencing from blood samples, and observed, at 99.8% specificity, high early sensitivity soon after diagnosis (Day 3–7 = 85.1% [95% CI = 79.9–89.7]; Day 8–14 = 94.8% [90.7–98.4]) as well as lasting sensitivity after recovery (Day 29+/convalescent = 95.4% [92.1–98.3]).DiscussionThe approaches described in this work provide detailed insights into the adaptive immune response to SARS-CoV-2 infection, and they have potential applications in clinical diagnostics, vaccine development, and monitoring.

AIM: To compare the efficacy and safety of ceftazidime-avibactam (CAZ/AVI) and meropenem-vaborbactam (MER/VAB) in treating carbapenem-resistant Enterobacterales (CRE) infections. BACKGROUND: CRE infections pose significant clinical challenges due to limited treatment options. CAZ/AVI and MER/VAB are recommended therapies, yet robust data comparing these treatments are lacking. METHODS: Multicentric retrospective cohort study on patients treated with CAZ/AVI or MER/VAB for microbiologically documented CRE infections between 2018 and 2024, enrolled in the SUSANA (Surveillance of Safety and Outcome of New Antibiotics) cohort.Collected data included demographics, treatment regimens, infection sites, pathogens, clinical outcomes and adverse events (AE). RESULTS: One-hundred sixty-eight patients were enrolled (131 in CAZ/AVI, 37 in MER/VAB), with 62.6% and 62.2% males, respectively. Median age was 68 years in CAZ/AVI and 70 in MER/VAB. Median Charlson Comorbidity Index was 5 in both groups. [Fig.1]Most infections were respiratory, genitourinary, or abdominal. Klebsiella spp. was the predominant pathogen (CAZ/AVI: 98.5%, MER/VAB: 100%) with high prevalence of KPC-producing strains (82.2%; 73.0%, respectively). [Fig.2]Clinical success was comparable, with patients in CAZ/AVI achieving 67.9% clinical cure versus 64.9% in MER/VAB, while in-hospital mortality was 20.6% vs 29.7% and relapse 11.5% vs 5.4%, respectively (p-value=0.343). No differences were found after accounting for site of infection [Fig.3]. AE were similar between groups. Kaplan-Meier survival curves (Fig.4) showed no significant difference in overall 28-day survival (19.1% vs 27.0%, log-rank p=0.343) between the two groups. CONCLUSION: CAZ/AVI and MER/VAB are effective treatments for CRE infection, demonstrating similar clinical outcomes. Further prospective studies are needed to validate these findings.

Summary: A Delphi consensus-seeking procedure was conducted to validate a list of ICD-9-CM codes that could help identify hospital admissions in which antimicrobials are more likely to be prescribed. The panel agreed to include 2967 codes out of 16229 (18.28%). Such codes could support AMS strategies by large-scale monitoring of drug consumption.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Summary: Background: Severe and prolonged mpox courses have been described during the 2022–2023 outbreak. Identifying predictors of severe evolution is crucial for improving management and therapeutic strategies. We explored the predictors of mpox severity and tested the association between mpox severity and viral load in biological fluids. We also analysed the predictors of disease duration and kinetics of inflammatory markers and described the viral presence and duration of shedding in biological fluids. Methods: This multicentre historical cohort study included adults diagnosed with laboratory-confirmed mpox diagnosis between May 2022 and September 2023 at 15 Italian centres. Patients were followed up from the day of diagnosis until clinical recovery. Biological fluids (blood, urine, saliva, and oropharyngeal and rectal swabs) were collected from each subgroup during the course of the disease and after healing. The primary outcomes were disease severity (presence of mucosal involvement, extended rash, or need for hospitalisation) and its association with the cycle threshold value (Ct-value, surrogate of viral load) in biological fluids, using standard linear and linear mixed-effect logistic regression models. Among the secondary outcomes, predictors of disease duration were assessed using a linear regression model. Findings: A total of 541 patients were enrolled, including four (0.74%) women, with a median age of 38 years (IQR 33–44). Among the 235 people living with HIV (PLWH) (43.44%), 22 (4.07%) had a CD4 count lower than 350 cells/μL. Severe mpox was reported in 215 patients (39.74%). No patient died. Multivariable analysis showed that, severe mpox was more likely among Caucasians (OR 1.82; 95% CI 1.14–2.90, p = 0.012) and patients who had an onset of fever (1.95; 1.27–2.99, p = 0.002), lymphadenopathy (2.30; 1.52–3.48, p

Background: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. Methods: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson’s Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. Results: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039–0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582–1.703, p = 0.987). Conclusions: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

Transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis and raphe-type bicuspid aortic valve (BAV) is still associated with poor outcomes in terms of increased risk of paravalvular regurgitation, stroke, and permanent pacemaker implantation. There is no definitive consensus on the optimal sizing method for prosthesis selection in this setting. The LIRA method is a supra-annular tailored sizing method specifically designed for bicuspid anatomy that might increase accuracy of prosthesis choice in BAV patients and improve TAVR outcomes. This is the first report of the combination of the novel LIRA method for prosthesis sizing together with the adoption of the technological improvements introduced by the Evolut FX prosthesis as a useful tool for improving outcomes in this high risk subgroup of patients.

Objective: Monoclonal antibodies (mAbs) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reduced Coronavirus Disease 2019 (COVID-19) hospitalizations in people at risk of clinical worsening. Real-world descriptions are limited. Methods: CONDIVIDIAMO, a two-year multicenter observational study, consecutively enrolled SARS-CoV-2 outpatients with ≥1 risk factor for COVID-19 progression receiving mAbs. Demographic data, underlying medical condition, type of mAbs combination received, duration of symptoms before mAbs administration, COVID-19 vaccination history, were collected upon enrolment and centrally recorded. Data on outcomes (hospitalizations, reasons of hospitalization, deaths) were prospectively collected. The primary endpoint was the rate of hospitalization or death in a 28-day follow-up, whichever occurred first; subjects were censored at the day of last follow-up or up to 28 days. The Kaplan-Meier method was used to estimate the incidence rate curve in time. The Cox regression model was used to assess potential risk factors for unfavorable outcome. Results were shown as hazard ratio (HR) along with the corresponding 95 % Confidence Interval (95%CI). Results: Among 1534 subjects (median [interquartile range, IQR] age 66.5 [52.4–74.9] years, 693 [45.2 %] women), 632 (41.2 %) received bamlanivimab ± etesevimab, 209 (13.6 %) casirivimab/imdevimab, 586 (38.2 %) sotrovimab, 107 (7.0 %) tixagevimab/cilgavimab. After 28-day follow-up, 87/1534 (5.6 %, 95%CI: 4.4%–6.8 %) met the primary outcome (85 hospitalizations, 2 deaths). Hospitalizations for COVID-19 (52, 3.4 %) occurred earlier than for other reasons (33, 2.1 %), after a median (IQR) of 3.5 (1–7) versus 8 (3–15) days (p = 0.006) from mAbs administration.In a multivariable Cox regression model, factors independently associated with increased hospitalization risk were age (hazard ratio [HR] 1.02, 95%CI 1.00–1.03, p = 0.021), immunodeficiency (HR 1.78, 95%CI 1.11–2.85, p = 0.017), pre-Omicron calendar period (HR 1.66, 95%CI 1.02–2.69, p = 0.041). Conclusions: MAbs real-world data over a 2-year changing pandemic landscape showed the feasibility of the intervention, although the hospitalization rate was not negligible. Immunosuppressed subjects remain more at risk of clinical worsening.

Background: European countries have included healthcare workers (HCWs) among priority groups for COVID-19 vaccination. We established a multi-country hospital network to measure the SARS-CoV-2 incidence and effectiveness of COVID-19 vaccines among HCWs against laboratory-confirmed SARS-CoV-2 infection. Methods: HCWs from 19 hospitals in 10 countries participated in a dynamic prospective cohort study, providing samples for SARS-CoV-2 testing at enrolment and during weekly/fortnightly follow-up. We measured the incidence during pre-Delta (2 May–6 September 2021), Delta (7 September–14 December 2021), and Omicron (15 December 2021–2 May 2023) waves. Using Cox regression, we measured the relative vaccine effectiveness (rVE) of the first COVID-19 booster dose versus primary course alone during Delta and Omicron waves. Results: We included a total of 3015 HCWs. Participants were mostly female (2306; 79%), with a clinical role (2047; 68%), and had a median age of 44 years. The overall incidence of SARS-CoV-2 infection was 3.01/10,000 person-days during pre-Delta, 4.21/10,000 during Delta, and 23.20/10,000 during Omicron waves. rVE was 59% (95% CI: −25; 86) during Delta and 22% (1; 39) during Omicron waves. rVE was 51% (30; 65) 7–90 days after the first booster dose during the Omicron wave. Conclusions: The incidence of SARS-CoV-2 infection among HCWs was higher during the Omicron circulation period. The first COVID-19 vaccine booster provided additional protection against SARS-CoV-2 infection compared to primary course vaccination when recently vaccinated

Abstract Introduction Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. Methods In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. Results Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. Conclusions This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. Trial Registration ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51. Graphical Abstract

Background: Mpox virus (MPXV) has recently spread outside of sub-Saharan Africa. This large multicentre study was conducted in Lombardy, the most densely populated Italian region accounting for more than 40% of Italian cases. The present study aims to: i) evaluate the presence and the shedding duration of MPXV DNA in different body compartments correlating the MPXV viability with the time to onset of symptoms; ii) provide evidence of MPXV persistence in different body compartment as a source of infection and iii) characterize the MPXV evolution by whole genome sequencing (WGS) during the outbreak occurred in Italy. Material and methods: The study included 353 patients with a laboratory-confirmed diagnosis of MPXV infection screened in several clinical specimens in the period May 24th - September 1st, 2022. Viral isolation was attempted from different biological matrices and complete genome sequencing was performed for 61 MPXV strains. Results: MPXV DNA detection was more frequent in the skin (94.4%) with the longest median time of viral clearance (16 days). The actively-replicating virus in cell culture was obtained for 123/377 (32.6%) samples with a significant higher viral quantity on isolation positive samples (20 vs 31, p

Hospital-acquired pneumonia (HAP) and ventilation-associated pneumonia (VAP) are challenging clinical conditions due to the challenging tissue penetrability of the lung. This study aims to evaluate the potential role of fosfomycin (FOS) associated with ceftazidime/avibactam (CZA) in improving the outcome in this setting. We performed a retrospective study including people with HAP or VAP treated with CZA or CZA+FOS for at least 72 h. Clinical data were collected from the SUSANA study, a multicentric cohort to monitor the efficacy and safety of the newer antimicrobial agents. A total of 75 nosocomial pneumonia episodes were included in the analysis. Of these, 34 received CZA alone and 41 in combination with FOS (CZA+FOS). People treated with CZA alone were older, more frequently male, received a prolonged infusion more frequently, and were less frequently affected by carbapenem-resistant infections (p = 0.01, p = 0.06, p < 0.001, p = 0.03, respectively). No difference was found in terms of survival at 28 days from treatment start between CZA and CZA+FOS at the multivariate analysis (HR = 0.32; 95% CI = 0.07–1.39; p = 0.128), while prolonged infusion showed a lower mortality rate at 28 days (HR = 0.34; 95% CI = 0.14–0.96; p = 0.04). Regarding safety, three adverse events (one acute kidney failure, one multiorgan failure, and one urticaria) were reported. Our study found no significant association between combination therapy and mortality. Further investigations, with larger and more homogeneous samples, are needed to evaluate the role of combination therapy in this setting.

Abstract Background Doravirine (DOR) is a newly approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI), well tolerated and leading to an improved lipid profile in antiretroviral experienced people living with HIV (PLWH). We aimed at evaluating if the lipid-lowering effect is linked to the drug class, using real-life data from the SCOLTA cohort. Methods We compared the lipid profile modifications in experienced PLWH switching to a DOR-based regimen from rilpivirine or another NNRTI-based regimen or from an integrase strand transferase (INSTI)-based regimen. T0 and T1 were defined as the baseline and 6-month follow-up respectively. Data were collected at baseline and prospectively every six months and changes from baseline were compared using a multivariable linear model. Results In 107 PLWH, enrolled in the SCOLTA DOR cohort, with undetectable HIV-RNA at baseline, 32.7% switched from RPV-based regimens (DOR1), 29.9% from other NNRTI-including regimens (DOR2) and 37.4% switched from INSTI-including regimens (DOR3). At T1, TC significantly decreased in DOR2 (-15 mg/dL) and DOR3 (-23 mg/dL), and significantly more in DOR3 than in DOR1 (-6 mg/dL) (p = 0.016). HDL-C declined in DOR2 (-2 mg/dL) whereas it increased in DOR1 (+ 3 mg/dL) (p = 0.042) and remained stable in DOR3. LDL-C significantly decreased from baseline in DOR2 (-12 mg/dL) and DOR3 (-22 mg/dL) and was different between DOR1 (-8 mg/dL) and DOR3 (p = 0.022). TC/HDL ratio showed a significant decline in the DOR3 group (-0.45), although similar to DOR1 (-0.23, p = 0.315) and DOR2 (-0.19, p = 0.254). Triglycerides did not noticeably change. ALT significantly decreased in PLWH with a baseline level > 40 UI/mL. Conclusions PLWH on doravirine treatment showed different trends in blood lipids according to their previous regimen. In PLWH switching from RPV, minimal modifications were seen, whereas in those switching from other NNRTIs and from INSTI-including regimens, we observed an overall improvement in lipid profile, seemingly independent of the “statin effect” of TDF.

Abstract Background Combined antiretroviral therapy (cART) dramatically improved survival in people living with HIV (PLWH) but is associated with weight gain (WG), raising concern for a possible obesity epidemic in PLWH. This scoping review aims to identify the gaps in the existing evidence on WG in PLWH and generate a future research agenda. Methods This review was conducted according to the methodology for scoping studies and reported according to the PRISMA Extension for Scoping Review checklist. Articles published in English in the last 10 years indexed in Pubmed, WHO Global Index Medicus, or Embase were searched using specific queries focused on WG in PLWH. Results Following the selection process, 175 included articles were reviewed to search for the available evidence on four specific topics: (I) definition of WG in PLWH, (II) pathogenesis of WG in PLWH, (III) impact of ART on WG, (IV) correlation of WG with clinical outcomes. A summary of the data enabled us to identify gaps and clearly define the following research agenda: (I) develop a data-driven definition of WG in PLWH and define noninvasive assessment methods for body weight and fat composition; (II) further investigate the interaction between HIV/cART and immunity, metabolism, and adipose tissue; (III) establish the specific role of individual drugs on WG; (IV) clarify the independent role of WG, cART, HIV, and metabolic factors on clinical events. Conclusions The proposed research agenda may help define future research and fill the knowledge gaps that have emerged from this review.

Abstract Background Post-COronaVIrus Disease 2019 (COVID-19) conditions (PCC) include multiple symptoms afflicting different organs and systems. To evaluate the frequency and type of them, we described our multidisciplinary approach with preliminary results of the first enrolled patients. Methods We included patients aged ≥ 18 years with hospital admission for confirmed SARS-CoV-2 infection. Symptoms were grouped in five macro groups hereafter referred to as "Symptoms Category" (SC): respiratory SC (dyspnoea or cough), neurological SC (peripheral neuropathies, headache, impaired mobility, behavioural disorders), psychological SC (sleep disorders, mood disorders), muscular SC (arthromyalgia, asthenia), other SC (fever, alopecia, diarrhoea, weight loss, smell and taste alterations, sexual dysfunctions). SC were evaluated at discharge and at follow-up. Association between patients’ characteristics and presence of SC at follow up was estimated by a logistic multivariable regression model. Results From June 2020 to July 2021, we followed up 361 patients: 128 (35.5%) who were previously admitted to Intensive Care Unit (ICU) and 233 patients to ordinary department. The median length of hospital stay was 20 days (Inter-Quartile-Range 13–32). Most patients (317/361, 87.8%) were still symptomatic at discharge, with one third referring three or more SC. At follow up, 67.3% (243/361) of patients still complained at least one SC. Moreover, 159 patients (44%) developed at least one new involved SC during follow up: 116 (72.9%) one SC, 39 (24.5%) two SC, 4 (2.5%) three or more SC. At follow up visit 130 of 361 (36%) were still with SC developed during follow up. At multivariable analysis presence of any SC at follow-up was associated with male gender (Odds Ratio [OR] 3.23, Confidence Interval [CI] 95% 1.46–7.15), ICU admission (OR 2.78, CI 95% 1.29–5.96) and presence of SC at discharge (OR 14.39, CI 95% 6.41–32.32). Conclusions In our sample of patients with severe COVID-19, we found that PCC are highly variable and fluctuating over time; in particular, in about 50% of our patients new SC appear during follow up. Moreover, presence of PCC also in patients without SC at discharge and the variability of symptoms underlining the advisability of our multidisciplinary approach. Trial registration number: ClinicalTrials.gov Identifier: NCT04424992, registered on 28 February 2020 https://www.clinicaltrials.gov/ct2/results?recrs=ab&cond=&term=NCT04424992&cntry=&state=&city=&dist The current version of protocol is version 1.0 enrolling since June 2020. The enrollment is still ongoing.

ObjectiveSepsis and septic shock are major challenges and economic burdens to healthcare, impacting millions of people globally and representing significant causes of mortality. Recently, a large number of quality improvement programs focused on sepsis resuscitation bundles have been instituted worldwide. These educational initiatives have been shown to be associated with improvements in clinical outcomes. We aimed to evaluate the impact of a multi-faceted quality implementing program (QIP) on the compliance of a “simplified 1-h bundle” (Sepsis 6) and hospital mortality of severe sepsis and septic shock patients out of the intensive care unit (ICU).MethodsEmergency departments (EDs) and medical wards (MWs) of 12 academic and non-academic hospitals in the Lombardy region (Northern Italy) were involved in a multi-faceted QIP, which included educational and organizational interventions. Patients with a clinical diagnosis of severe sepsis or septic shock according to the Sepsis-2 criteria were enrolled in two different periods: from May 2011 to November 2011 (before-QIP cohort) and from August 2012 to June 2013 (after-QIP cohort).Measurements and main resultsThe effect of QIP on bundle compliance and hospital mortality was evaluated in a before–after analysis. We enrolled 467 patients in the before-QIP group and 656 in the after-QIP group. At the time of enrollment, septic shock was diagnosed in 50% of patients, similarly between the two periods. In the after-QIP group, we observed increased compliance to the “simplified rapid (1 h) intervention bundle” (the Sepsis 6 bundle – S6) at three time-points evaluated (1 h, 13.7 to 18.7%, p = 0.018, 3 h, 37.1 to 48.0%, p = 0.013, overall study period, 46.2 to 57.9%, p

Background: Meeting the challenge of antiretroviral therapy (ART) whose efficacy can last a lifetime requires continuous updating of the virological, pharmacological, and quality of life outcomes to be pursued and a continuous review of literature data on the efficacy and tolerability of new drugs and therapeutic strategies. Methods: With the aim of identifying open questions and answers about the current controversies in modern ART, we adapted the Design Thinking methodology to the needs of the design phase of a scientific article, involving a team of experts in HIV care. Results: Five main pillars of treatment success were discussed: sustained virologic suppression over time; immunological recovery; pharmacological attributes; long-term tolerability and safety of ART; and people’s satisfaction and quality of life. The definition of the outcomes to be achieved in each thematic area and the tools to achieve them were reviewed and discussed. Conclusions: Long-term treatment success should be intended as a combination of HIV-RNA suppression, immune recovery, and high quality of life. To achieve this, the regimen should be well-tolerated, with high potency, genetic barrier, and forgiveness, and should be tailored by a person-centered perspective, based on individual needs, preferences, and therapeutic history.

Background: The coexistence of HIV infection and latent tuberculosis infection (LTBI) presents a significant public health concern due to the increased risk of tuberculosis (TB) reactivation and progression to active disease. The multicenter observational cohort study, TUBHIVIT, conducted in Italy from 2017 to 2023, aimed to assess the prevalence of LTBI among people living with HIV (PLHIV) and their outcomes following LTBI screening and therapy initiation. Methods: We performed a prospective study in five referral centers for HIV care in Italy. PLHIV who consented Tto participate underwent QuantiFERON-TB Gold Plus and clinical, microbiological, and radiological assessments to exclude subclinical tuberculosis, as opportune. PLHIV diagnosed with LTBI who started chemoprophylaxis were followed until the end of therapy. Results: A total of 1105 PLHIV were screened for LTBI using the QuantiFERON-TB Gold Plus test, revealing a prevalence of 3.4% of positive results (38/1105). Non-Italy-born individuals exhibited a significantly higher likelihood of testing positive. Thirty-one were diagnosed with LTBI, 1 showed active subclinical TB, and 6 were lost to follow-up before discriminating between latent and active TB. Among the PLHIV diagnosed with LTBI, 83.9% (26/31) started chemoprophylaxis. Most individuals received 6–9 months of isoniazid-based therapy. Of the 26 PLHIV commencing chemoprophylaxis, 18 (69.2%) completed the therapy, while 3 discontinued it and 5 were still on treatment at the time of the analysis. Adverse events were observed in two cases, while in one case the patient refused to continue the treatment.

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.

Abstract Background In persons living with HIV (PLWH), the burden of non-communicable chronic diseases increased over time, because of aging associated with chronic inflammation, systemic immune activation, and long-term exposure to the combination antiretroviral therapy (ART). Methods To explore the association of chronological age, age at first ART, and exposure to ART with non-communicable chronic diseases, we performed a cross-sectional analysis to evaluate the prevalence of comorbidities in patients enrolled in the SCOLTA Project, stratified by groups of chronological age (50–59 and 60–69 years) and by years of antiretroviral treatment (ART, ≤ 3 or > 3 years). Results In 1394 subjects (23.8% women), mean age at enrollment was 57.4 (SD 6.5) years, and at first ART 45.3 (SD 10.7). Men were older than women both at enrollment (57.6 vs 56.8, p = 0.06) and at first ART (45.8 vs 43.6, p = 0.0009). ART duration was longer in women (13.1 vs 11.7 years, p = 0.01). The age- and sex-adjusted rate ratios (aRRs, and 95% confidence interval, CI) showed that longer ART exposure was associated with dyslipidemia (aRR 1.35, 95% CI 1.20–1.52), hypertension (aRR 1.52, 95% CI 1.22–1.89), liver disease (aRR 1.78, 95% CI 1.32–2.41), osteopenia/osteoporosis (aRR 2.88, 95% CI 1.65–5.03) and multimorbidity (aRR 1.36, 95% CI 1.21–1.54). These findings were confirmed in strata of age, adjusting for sex. Conclusions Our data suggest that longer ART exposure was associated with increased risk of dyslipidemia, hypertension, and osteopenia/osteoporosis, hence the presence of multimorbidity, possibly due to the exposition to more toxic antiretrovirals. We observed different comorbidities, according to ART exposure and age.

Background Prone positioning is routinely used among patients with COVID-19 requiring mechanical ventilation. However, its utility among spontaneously breathing patients is still debated. Methods In an open-label randomised controlled trial, we enrolled patients hospitalised with mild COVID-19 pneumonia, whose arterial oxygen tension to inspiratory oxygen fraction ratio (PaO2/FIO2) was >200 mmHg and who did not require mechanical ventilation or continuous positive airway pressure at hospital admission. Patients were randomised 1:1 to prone positioning on top of standard of care (intervention group) versus standard of care only (controls). The primary composite outcome included death, mechanical ventilation, continuous positive airway pressure and PaO2/FIO2

Abstract Discontinuation of antimicrobial stewardship programs (ASPs) and increased antibiotic use were described during SARS-CoV-2 pandemic. In order to measure COVID-19 impact on ASPs in a setting of high multidrug resistance organisms (MDRO) prevalence, a qualitative survey was designed. In July 2021, eighteen ID Units were asked to answer a questionnaire about their hospital characteristics, ASPs implementation status before the pandemic and impact of SARS-CoV-2 pandemic on ASPs after the 1st and 2nd pandemic waves in Italy. Nine ID centres (50%) reported a reduction of ASPs and in 7 cases (38.9%) these were suspended. After the early pandemic waves, the proportion of centres that restarted their ASPs was higher among the ID centres where antimicrobial stewardship was formally identified as a priority objective (9/11, 82%, vs 2/7, 28%). SARS-CoV-2 pandemic had a severe impact in ASPs in a region highly affected by COVID-19 and antimicrobial resistance but weaknesses related to the pre-existent ASPs might have played a role.

The recent Mpox virus (MPV) outbreak in Europe and North America, primarily among men who have sex with men (MSM), raised concerns about various transmission sources. We examined patients with Mpox from an urban STI center in Lombardy, Italy, between May and August 2022. Demographic, transmission, and clinical data were collected using a standardized form. Initial and subsequent tests were conducted using the RealStar Orthopoxvirus PCR Kit 1.0 (Altona Diagnostics, Hamburg, Germany) for skin lesions and oropharyngeal swabs. A total of 15 patients were recruited, all MSM, with 40% being HIV-positive. Almost all reported recent unprotected sexual activity. Oropharyngeal symptoms were observed in a minority, and oral cavity lesions were present in 20% of cases. MPV DNA was detected in skin lesions of 93% of patients and in oropharyngeal swabs of 87%. Skin samples exhibited a higher viral load than pharyngeal samples, with the latter persisting longer. Prospective follow-up of 11 individuals revealed an average pharyngeal persistence of 5.3 days beyond skin lesion clearance, reaching up to 80 days in an immunosuppressed case. Our findings indicate that MPV replication can persist in the pharynx asymptomatically and for an extended period.

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real‐life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE‐Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow‐up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03‐1.09) and diabetes (OR 2.01 [1.65‐2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35‐0.60]; P

ObjectivesThe development of novel antiviral agents active against Hepatitis Delta Virus (HDV) might change the natural history of chronic infection, reducing the risk for end-stage liver disease. People living with HIV (PWH) are at risk for bloodborne pathogens infection, but limited data on epidemiology of HDV infection is available in this setting. The aim of this study was to investigate HDV prevalence and attitude toward HDV testing and treatment in infectious diseases centers.MethodsA cross sectional survey was performed among centers participating in the CISAI (Coordinamento Italiano per lo Studio dell’Allergia in Infezione da HIV) Group. The survey addressed anti-HDV prevalence and HDV-RNA detectability rates in PWH as well as perceived obstacles to treatment.ResultsOverall, responses from ten sites were collected. Among participating centers, 316 PWH with HBV chronic infection are currently followed. Of them, 15.2% had positive anti-HDV antibodies, while 13.9% were not tested yet. Overall, 17% of anti-HDV positive PWH tested at least once for HDV-RNA had active HDV infection, and 71% of them had advanced liver disease. Most infectious diseases centers intend to treat locally HDV infection with upcoming anti-HDV drugs, but some concerns exist regarding treatment schedule.DiscussionHDV testing needs to be implemented in PWH. At present, few patients followed in the CISAI centers seem to be candidate to receive new direct active anti-HDV agents, but repeated HDV-RNA measures could change this proportion.

BackgroundPTX3 is an important mediator of inflammation and innate immunity. We aimed at assessing its prognostic value in a large cohort of patients hospitalized with COVID-19.MethodsLevels of PTX3 were measured in 152 patients hospitalized with COVID-19 at San Gerardo Hospital (Monza, Italy) since March 2020. Cox regression was used to identify predictors of time from admission to in-hospital death or mechanical ventilation. Crude incidences of death were compared between patients with PTX3 levels higher or lower than the best cut-off estimated with the Maximally Selected Rank Statistics Method.ResultsUpon admission, 22% of the patients required no oxygen, 46% low-flow oxygen, 30% high-flow nasal cannula or CPAP-helmet and 3% MV. Median level of PTX3 was 21.7 (IQR: 13.5-58.23) ng/ml. In-hospital mortality was 25% (38 deaths); 13 patients (8.6%) underwent MV. PTX3 was associated with risk of death (per 10 ng/ml, HR 1.08; 95%CI 1.04-1.11; P

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as “COVID toes,” remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19–affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI). We aimed to investigate, in a real-life setting, how switching to a DOR-based regimen rather than a rilpivirine (RPV)-based regimen impacted metabolic and hepatic safety. The analysis included 551 antiretroviral treatment (ART)-experienced people living with HIV (PLWH), starting RPV-based or DOR-based regimens with viral load < 200 copies/mL, baseline (T0), and at least one control visit (6-month visit, T1). We enrolled 295 PLWH in the RPV and 256 in the DOR cohort. At T1, total cholesterol (TC), low-density lipoprotein-C (LDL-C), and triglycerides significantly decreased in both DOR and RPV cohorts, while high-density lipoprotein-C (HDL-C) only decreased in RPV-treated people. Consistently, the TC/HDL-C ratio declined more markedly in the DOR (−0.36, p < 0.0001) than in the RPV cohort (−0.08, p = 0.25) (comparison p = 0.39). Similar trends were observed when excluding the PLWH on lipid-lowering treatment from the analysis. People with normal alanine aminotransferase (ALT) levels showed a slight ALT increase in both cohorts, and those with baseline ALT > 40 IU/L experienced a significant decline (−14 IU/L, p = 0.008) only in the DOR cohort. Lipid profile improved in both cohorts, and there was a significant reduction in ALT in PLWH with higher-than-normal baseline levels on DOR-based ART.

Klebsiella pneumoniae carbapenemase–producing K. pneumoniae (KPC-Kp) has been endemic in Italy since 2013. In a multicenter cohort study, we investigated various aspects of KPC-Kp among patients, including 15-day mortality rates and delays in adequate therapy. Most (77%) KPC-Kp strains were sequence type (ST) ST512 or ST307. During 2017, KPC-Kp prevalence was 3.26 cases/1,000 hospitalized patients. Cumulative incidence of KPC-Kp acquired >48 hours after hospital admission was 0.68% but varied widely between centers. Among patients with mild infections and noninfected colonized patients, 15-day mortality rates were comparable, but rates were much higher among patients with severe infections. Delays of >4 days in receiving adequate therapy more frequently occurred among patients with mild infections than those with severe infections, and delays were less common for patients with known previous KPC-Kp colonization. Italy urgently needs a concerted surveillance system to control the spread of KPC-Kp.

Abstract Background Respiratory failure due to COVID-19 pneumonia is associated with high mortality and may overwhelm health care systems, due to the surge of patients requiring advanced respiratory support. Shortage of intensive care unit (ICU) beds required many patients to be treated outside the ICU despite severe gas exchange impairment. Helmet is an effective interface to provide continuous positive airway pressure (CPAP) noninvasively. We report data about the usefulness of helmet CPAP during pandemic, either as treatment, a bridge to intubation or a rescue therapy for patients with care limitations (DNI). Methods In this observational study we collected data regarding patients failing standard oxygen therapy (i.e., non-rebreathing mask) due to COVID-19 pneumonia treated with a free flow helmet CPAP system. Patients’ data were recorded before, at initiation of CPAP treatment and once a day, thereafter. CPAP failure was defined as a composite outcome of intubation or death. Results A total of 306 patients were included; 42% were deemed as DNI. Helmet CPAP treatment was successful in 69% of the full treatment and 28% of the DNI patients (P

Abstract Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P

Abstract Background Tobacco use is a leading cause of preventable diseases and death for all individuals, even more so for people living with HIV (PLWH), due to their status of chronic inflammation. To date, in Italy no study was performed to compare smoking habits in PLWH and the general population. We aimed to investigate smoking habits in PLWH, as compared to the general population. Methods Multi-center cross-sectional study. Smoking habits were compared between PLWH and the general population. PLWH were enrolled in the STOPSHIV Study. The comparison group from the general population was derived from a survey performed by the National Statistics Institute (ISTAT), with a stratified random sampling procedure matching 2:1 general population subjects with PLWH by age class, sex, and macro-area of residence. Results The total sample consisted of 1087 PLWH (age 47.9 ± 10.8 years, male 73.5%) and 2218 comparable subjects from the general population. Prevalence of current smokers was 51.6% vs 25.9% (p 20 cigarettes per day) (aOR = 4.84; 95% CI = 3.74–6.27; p

Summary: Background: In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab in COVID-19 beyond day 28 and its impact on Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) clearance and antibody response in COVACTA were investigated. Methods: Adults in Europe and North America hospitalised with COVID-19 (N = 452) between April 3, 2020 and May 28, 2020 were randomly assigned (2:1) to double-blind intravenous tocilizumab or placebo and assessed for efficacy and safety through day 60. Assessments included mortality, time to hospital discharge, SARS-CoV-2 viral load in nasopharyngeal swab and serum samples, and neutralising anti-SARS-CoV-2 antibodies in serum. ClinicalTrials.gov registration: NCT04320615. Findings: By day 60, 24·5% (72/294) of patients in the tocilizumab arm and 25·0% (36/144) in the placebo arm died (weighted difference –0·5% [95% CI –9·1 to 8·0]), and 67·0% (197/294) in the tocilizumab arm and 63·9% (92/144) in the placebo arm were discharged from the hospital. Serious infections occurred in 24·1% (71/295) of patients in the tocilizumab arm and 29·4% (42/143) in the placebo arm. Median time to negative reverse transcriptase–quantitative polymerase chain reaction result in nasopharyngeal/oropharyngeal samples was 15·0 days (95% CI 14·0 to 21·0) in the tocilizumab arm and 21·0 days (95% CI 14·0 to 28·0) in the placebo arm. All tested patients had positive test results for neutralising anti–SARS-CoV-2 antibodies at day 60. Interpretation: There was no mortality benefit with tocilizumab through day 60. Tocilizumab did not impair viral clearance or host immune response, and no new safety signals were observed. Future investigations may explore potential biomarkers to optimize patient selection for tocilizumab treatment and combination therapy with other treatments. Funding: F. Hoffmann-La Roche Ltd and the US Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under OT number HHSO100201800036C.

ObjectiveOur knowledge on the long-term consequences of COVID-19 is still scarce despite the clinical relevance of persisting syndrome. The aim of this study was to analyze patient-reported outcomes, including assessment by specific questionnaires of health impairment and symptoms.MethodsThis is a prospective, observational and multicenter cohort study coordinated by Fondazione IRCSS Ca' Granda Ospedale Maggiore Policlinico di Milano and Istituto di Ricerche Farmacologiche Mario Negri IRCCS including eight hospitals located in North and Central Italy. A telephone interview to assess rehospitalization, access to health care resources, general health status subjective evaluation, and symptoms was performed at 12 months after the discharge in patients admitted to hospital because of COVID-19 from February 2020 to the end of May 2020.ResultsAmong the 776 patients discharged alive, 44 (5.7%) died, 456 subjects (58.8%) completed the questionnaire and 276 (35.6%) were not reachable or refused to join the telephone interview. The mean age of the study population was 59.4 years (SD 14.1), 69.8% of individuals needed oxygen support during hospitalization and 10.4% were admitted to ICU. Overall, 91.7% of participants reported at least one symptom/sequela at 12 months. Exertional dyspnea (71.7%), fatigue (54.6%), and gastrointestinal symptoms (32.8%) were the most reported ones. Health issues after discharge including hospitalization or access to emergency room were described by 19.4% of subjects. Female and presence of comorbidities were independent predictors of whealth impairment and presence of ≥2 symptoms/sequelae after 12 months from hospitalization for COVID-19.ConclusionsPatient-reported symptoms and sequelae, principally dyspnea and fatigue, are found in most individuals even 12 months from COVID-19 hospitalization. Long-term follow-up based on patient-centered outcome can contribute to plan tailored interventions.

In the last years, many antiretroviral drugs (ART) have been developed with increased efficacy. Nowadays, the main reasons for treatment switches are adverse events, proactive strategy or simplification. We conducted a retrospective cohort study to investigate the reason for treatment interruption in the last 20 years. We merged data of eight cohorts of the SCOLTA project: lopinavir/r (LPV), atazanavir/r (ATV), darunavir/r or /c (DRV), rilpivirine (RPV), raltegravir (RAL), elvitegravir/c (EVG), dolutegravir (DTG) and bictegravir (BIC). We included 4405 people with HIV (PWH). Overall, 664 (15.1%), 489 (11.1%), and 271 (6.2%) PWH interrupted the treatment in the first, second, and third years after starting a new ART. Looking at the interruption in the first year, the most frequent causes were adverse events (3.8%), loss to follow-up (3.7%), patients’ decisions (2.6%), treatment failure (1.7%), and simplification (1.3%). In the multivariate analysis regarding experienced patients, treatment with LPV, ATV, RPV or EVG/c, having less than 250 CD4 cells/mL, history of intravenous drug use, and HCV positivity were associated with an increased risk of interruption. In naive people, only LPV/r was associated with an increased risk of interruption, while RPV was associated with a lower risk. In conclusion, our data on more than 4400 PWH show that adverse events have represented the most frequent cause of treatment interruptions in the first year of ART (3.84%). Treatment discontinuations were more frequent during the first year of follow-up and decreased thereafter. First-generation PI in both naïve and experienced PWH, and EVG/c, in experienced PWH, were associated with a higher risk of treatment interruptions.

Understanding the cause of sex disparities in COVID-19 outcomes is a major challenge. We investigate sex hormone levels and their association with outcomes in COVID-19 patients, stratified by sex and age. This observational, retrospective, cohort study included 138 patients aged 18 years or older with COVID-19, hospitalized in Italy between February 1 and May 30, 2020. The association between sex hormones (testosterone, estradiol, progesterone, dehydroepiandrosterone) and outcomes (ARDS, severe COVID-19, in-hospital mortality) was explored in 120 patients aged 50 years and over. STROBE checklist was followed. The median age was 73.5 years [IQR 61, 82]; 55.8% were male. In older males, testosterone was lower if ARDS and severe COVID-19 were reported than if not (3.6 vs. 5.3 nmol/L, p =0.0378 and 3.7 vs. 8.5 nmol/L, p =0.0011, respectively). Deceased males had lower testosterone (2.4 vs. 4.8 nmol/L, p =0.0536) and higher estradiol than survivors (40 vs. 24 pg/mL, p = 0.0006). Testosterone was negatively associated with ARDS (OR 0.849 [95% CI 0.734, 0.982]), severe COVID-19 (OR 0.691 [95% CI 0.546, 0.874]), and in-hospital mortality (OR 0.742 [95% CI 0.566, 0.972]), regardless of potential confounders, though confirmed only in the regression model on males. Higher estradiol was associated with a higher probability of death (OR 1.051 [95% CI 1.018, 1.084]), confirmed in both sex models. In males, higher testosterone seems to be protective against any considered outcome. Higher estradiol was associated with a higher probability of death in both sexes.

The pathogenesis of COVID-19 appears to be characterized by a dysregulated immune response. During the first pandemic wave in Lombardy, we started to administer glucocorticoids to some patients with severe respiratory failure requiring support with Continuous Positive Airway Pressure (CPAP) therapy. We retrospectively collected data to identify the effect of glucocorticoids in this COVID-19 particular population. With a multidisciplinary consensus, we administered to selected patients with severe COVID-19 disease (PaO2/FiO2 159±71 mmHg) 0,91 mg/kg/die of methylprednisolone equivalent dose after a median of 8 days of hospitalization. In our study we compared 57 patients from the steroid group with 123 from the control group: the event of invasive mechanical ventilation or death was reduced by 43% between steroid group and control group (19.3 % vs. 34.1 % respectively, p=0.001) and mortality was reduced by about 31% between steroid and usual care alone (15.8 % vs. 22.8 % respectively, p=0.011). Corticosteroids in selected COVID-19 patients may have a relevant impact on outcome, better profiling of the heterogeneity of this disease may be essential to guarantee the best treatment choices.

Abstract Background Study aim was to evaluate the safety and durability of darunavir/cobicistat (DRV/c) in a real life setting. Methods Multicentre prospective cohort study performed in the context of SCOLTA (Surveillance Cohort Long-Term Toxicity Antiretrovirals). Patients were evaluated at baseline, week 24 and 48. Changes were evaluated using the paired t test or signed rank test. The multivariable analysis was performed using a general linear model, after ranking of not normally distributed variables. Results A total of 249 patients were included, 72 (29%) were in DRV/c-based dual therapies (DT). Hypercholesterolemia, HC, (total cholesterol (TC) ≥ 200 mg/dL or low density-C (LDL-C) ≥ 130 or statin use) was present in 121 (48.6%) and hypertriglyceridemia, (triglycerides (TG) ≥ 200 mg/dl or fibrate use) in 41 (16.5%) patients. Blood lipid profile did not change significantly in either the global population or patients with HC. After a median observation of 17 months (IQR 13–20), 59 (25.3%) patients discontinued DRV/c, of which 13 were in DT. The durability DT resulted higher than that of triple therapy (log-rank test p = 0.01). Main reasons for stopping DRV/c were simplification (15 patients), adverse events (13 patients), planned discontinuation for treatment initiation with DAA (4 patients), treatment failure (2 patients); death (2 patients), other causes (10 patients). Twenty-six were lost to follow-up. Conclusions DRV/c was safe and well tolerated. Dual therapies showed a better profile of tolerability and a longer durability compared to triple therapies.

Abstract Background Among people living with HIV (PLWH), the prevalence of non-HIV related co-morbidities is increasing. Aim of the present study is to describe co-morbidity and multi-morbidity, their clustering mode and the potential disease-disease interactions in a cohort of Italian HIV patients. Methods Cross-sectional analysis conducted by the Coordinamento Italiano per lo Studio di Allergia e Infezioni da HIV (CISAI) on adult subjects attending HIV-outpatient facilities. Non-HIV co-morbidities included: cardiovascular disease, diabetes mellitus, hypertension, oncologic diseases, osteoporosis, probable case of chronic obstructive pulmonary disease (COPD), hepatitis C virus (HCV) infection, psychiatric illness, kidney disease. Multi-morbidity was defined as the presence of two or more co-morbidities. Results One thousand and eighty-seven patients were enrolled in the study (mean age 47.9 ± 10.8). One hundred-ninety patients (17.5%) had no co-morbidity, whereas 285 (26.2%) had one condition and 612 (56.3%) were multi-morbid. The most recurrent associations were: 1) dyslipidemia + hypertension (237, 21.8%); 2) dyslipidemia + COPD (188, 17.3%); 3) COPD + HCV-Ab+ (141, 12.9%). Multi-morbidity was associated with older age, higher body mass index, current and former smoking, CDC stage C and longer ART duration. Conclusions More than 50% of PLHW were multi-morbid and about 30% had three or more concurrent comorbidities. The identification of common patterns of comorbidities address the combined risks of multiple drug and disease-disease interactions.

The aim of the present study was to evaluate CD4/CD8 dynamics in patients on dolutegravir (DTG)-based two-drug regimens (2DRs) and compare them with DTG-containing triple-drug regimens (3DRs). A prospective observational study was performed in the context of the SCOLTA cohort. Experienced PWH with HIV-RNA < 50 copies/mL were included if they were on the DTG-2DR, the DTG + tenofovir/emtricitabine (TDF/FTC) regimen, the DTG + tenofovir alafenamide (TAF)/FTC regimen, or the DTG + abacavir/lamivudine (ABC/3TC) regimen; they were followed-up for at least one year. A total of 533 PWH were enrolled, 120 in the DTG + 3TC group, 38 in the DTG + protease inhibitors (PI) group, 67 in the DTG + rilpivirine (RPV) group, 49 in the DTG + TDF/FTC group, 27 in the DTG + TAF/FTC group, and 232 in the DTG + ABC/3TC group. After one year, the CD4/CD8 ratio significantly increased in the PWH treated with DTG + 3TC (+0.08 ± 0.26), DTG + TDF/FTC (+0.1 ± 0.19), and DTG + ABC/3TC (+0.08 ± 0.25). At two years, the CD4/CD8 increase was confirmed for PWH on DTG + TDF/FTC (+0.16 ± 0.28) and DTG + ABC/3TC (+0.1 ± 0.3). In the SCOLTA cohort, PWH on 2DRs experienced a CD4/CD8 increase only in the DTG + 3TC group. Controlled studies with longer follow-up will clarify the long-term immunological and clinical impacts of DTG-2DR.

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients.Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients.Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores.Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs.Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

(1) Background: Among the different cardiovascular (CV) manifestations of the coronavirus disease 2019 (COVID-19), arrhythmia and atrial fibrillation (AF) in particular have recently received special attention. The aims of our study were to estimate the incidence of AF in patients hospitalized for COVID-19, and to evaluate its role as a possible predictor of in-hospital all-cause mortality. (2) Methods: We enrolled 3435 people with SARS-CoV2 infection admitted to three hospitals in Northern Italy from February 2020 to May 2021. We collected data on their clinical history, laboratory tests, pharmacological treatment and intensive care unit (ICU) admission. Incident AF and all-cause in-hospital mortality were considered as outcomes. (3) Results: 145 (4.2%) patients developed AF during hospitalization, with a median time since admission of 3 days (I-III quartile: 0, 12). Patients with incident AF were admitted more frequently to the ICU (39.3 vs. 12.4%, p < 0.001), and more frequently died (37.2 vs. 16.9%, p < 0.001). In the Cox regression model, the significant determinants of incident AF were age (HR: 1.041; 95% CI: 1.022, 1.060 per year), a history of AF (HR: 2.720; 95% CI: 1.508, 4.907), lymphocyte count (HR: 0.584; 95% CI: 0.384, 0.888 per 103/µL), estimated glomerular filtration rate (eGFR, HR: 0.988; 95% CI: 0.980, 0.996 per mL/min) and ICU admission (HR: 5.311; 95% CI: 3.397, 8.302). Incident AF was a predictor of all-cause mortality (HR: 1.405; 95% CI: 1.027, 1.992) along with age (HR: 1.057; 95% CI: 1.047, 1.067), male gender (HR: 1.315; 95% CI: 1.064; 1.626), dementia (HR: 1.373; 95% CI: 1.045, 1.803), lower platelet (HR: 0.997; 95% CI: 0.996, 0.998 per 103/µL) and lymphocyte counts (HR: 0.843; 95% CI: 0.725, 0.982 per 103/µL), C-Reactive protein values (HR: 1.004; 95% CI: 1.003, 1.005 per mg/L), eGFR (HR: 0.990; 95% CI: 0.986, 0.994 per mL/min), and ICU admission (HR: 1.759; 95% CI: 1.292, 2.395). (4) Conclusions: Incident AF is a common complication in COVID-19 patients during hospitalization, and its occurrence strongly predicts in-hospital mortality.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN–, type II IFN–, and NF-κB–dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.

BackgroundDuring the Coronavirus disease 2019 (COVID-19) pandemic, advanced health systems have come under pressure by the unprecedented high volume of patients needing urgent care. The impact on mortality of this "patients' burden" has not been determined.Methods and findingsThrough retrieval of administrative data from a large referral hospital of Northern Italy, we determined Aalen-Johansen cumulative incidence curves to describe the in-hospital mortality, stratified by fixed covariates. Age- and sex-adjusted Cox models were used to quantify the effect on mortality of variables deemed to reflect the stress on the hospital system, namely the time-dependent number of daily admissions and of total hospitalized patients, and the calendar period. Of the 1225 subjects hospitalized for COVID-19 between February 20 and May 13, 283 died (30-day mortality rate 24%) after a median follow-up of 14 days (interquartile range 5-19). Hospitalizations increased progressively until a peak of 465 subjects on March 26, then declined. The risk of death, adjusted for age and sex, increased for a higher number of daily admissions (adjusted hazard ratio [AHR] per an incremental daily admission of 10 patients: 1.13, 95% Confidence Intervals [CI] 1.05-1.22, p = 0.0014), and for a higher total number of hospitalized patients (AHR per an increase of 50 patients in the total number of hospitalized subjects: 1.11, 95%CI 1.04-1.17, p = 0.0004), while was lower for the calendar period after the peak (AHR 0.56, 95%CI 0.43-0.72, pConclusionsThe pressure of a high volume of severely ill patients suffering from COVID-19 has a measurable independent impact on in-hospital mortality.

The purpose of this study is to evaluate the frequency of central nervous system adverse events (CNS-AE) on dolutegravir (DTG) and non-DTG containing ART, and their reversibility, in the observational prospective SCOLTA cohort. Factors associated with CNS-AE were estimated using a Cox proportional-hazards model. 4939 people living with HIV (PLWH) were enrolled in DTG (n = 1179) and non-DTG (n = 3760) cohorts. Sixty-six SNC-AE leading to ART discontinuation were reported, 39/1179 (3.3%) in DTG and 27/3760 (0.7%) in non-DTG cohort. PLWH naïve to ART, with higher CD4 + T count and with psychiatric disorders were more likely to develop a CNS-AE. The risk was lower in non-DTG than DTG-cohort (aHR 0.33, 95% CI 0.19–0.55, p < 0.0001). One-year follow-up was available for 63/66 PLWH with CNS-AE. AE resolution was reported in 35/39 and 23/24 cases in DTG and non-DTG cohorts, respectively. The probability of AE reversibility was not different based on ART class, sex, ethnicity, CDC stage, or baseline psychiatric disorder. At the same time, a lower rate of event resolution was found in PLWH older than 50 years (p = 0.017). In conclusion, CNS-AE leading to ART discontinuation was more frequent in DTG than non-DTG treated PLWH. Most CNS-AE resolved after ART switch, similarly in both DTG and non-DTG cohorts.

Abstract Background Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1–3.7), with a significant decrease over time [2002–2006 = 3.3 yrs. (0.2–9.4); 2007–2011 = 1.0 yrs. (0.1–3.9); 2012–2016 = 0.2 yrs. (0.1–2.1), p