Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV).

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan-Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23-0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16-0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02-2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

A holistic evaluation of patients with chronic Hepatitis D virus (HDV) infection enrolled in the Italian PITER-B and Delta cohort.

BACKGROUND AND AIMS: We aimed to characterize the epidemiologic and comorbidities profiles of patients with chronic Hepatitis D (CHD) followed in clinical practice in Italy and explored their interferon (IFN) eligibility. METHODS: This was a cross-sectional study of the PITER cohort consisting of consecutive HBsAg-positive patients from 59 centers over the period 2019-2023. Multivariable analysis was performed by logistic regression model. RESULTS: Of 5,492 HBsAg-positive enrolled patients, 4,152 (75.6%) were screened for HDV, 422 (10.2%) were anti-HDV positive. Compared with HBsAg mono-infected, anti-HDV positive patients were more often younger, non-Italians, with a history of drug use, had elevated alanine transaminase (ALT), cirrhosis, or hepatocellular carcinoma (HCC). Compared with Italians, anti-HDV positive non-Italians were younger (42.2% age≤40 years vs. 2.1%; p<0.001), more often females (males 43.0% vs. 68.6%; p<0.001) with less frequent cirrhosis and HCC. HDV-RNA was detected in 63.2% of anti-HDV-positive patients, who were more likely to have elevated ALT, cirrhosis, and HCC. Extrahepatic comorbidities were present in 47.4% of anti-HDV positive patients and could affect the eligibility of IFN-containing therapies in at least 53.0% of patients in care. CONCLUSIONS: CHD affects young, foreign-born patients and older Italians, of whom two-thirds had cirrhosis or HCC. Comorbidities were frequent in both Italians and non-Italians and impacted eligibility for IFN.

Switching patterns of biological drugs in patients with psoriasis and psoriatic arthritis: insight from the VALORE database network.

BACKGROUND: Switch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA). OBJECTIVE: The aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back. RESEARCH DESIGN AND METHODS: A large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010-2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed. RESULTS: Thirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67-0.83; 0.58, 95% CI, 0.44-0.77, respectively) than those with TNF-α inhibitors. CONCLUSIONS: Patients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

CCL18, CHI3L1, ANG2, IL-6 systemic levels are associated with the extent of lung damage and radiomic features in SARS-CoV-2 infection.

OBJECTIVE AND DESIGN: We aimed to identify cytokines whose concentrations are related to lung damage, radiomic features, and clinical outcomes in COVID-19 patients. MATERIAL OR SUBJECTS: Two hundred twenty-six patients with SARS-CoV-2 infection and chest computed tomography (CT) images were enrolled. METHODS: CCL18, CHI3L1/YKL-40, GAL3, ANG2, IP-10, IL-10, TNFα, IL-6, soluble gp130, soluble IL-6R were quantified in plasma samples using Luminex assays. The Mann-Whitney U test, the Kruskal-Wallis test, correlation and regression analyses were performed. Mediation analyses were used to investigate the possible causal relationships between cytokines, lung damage, and outcomes. AVIEW lung cancer screening software, pyradiomics, and XGBoost classifier were used for radiomic feature analyses. RESULTS: CCL18, CHI3L1, and ANG2 systemic levels mainly reflected the extent of lung injury. Increased levels of every cytokine, but particularly of IL-6, were associated with the three outcomes: hospitalization, mechanical ventilation, and death. Soluble IL-6R showed a slight protective effect on death. The effect of age on COVID-19 outcomes was partially mediated by cytokine levels, while CT scores considerably mediated the effect of cytokine levels on outcomes. Radiomic-feature-based models confirmed the association between lung imaging characteristics and CCL18 and CHI3L1. CONCLUSION: Data suggest a causal link between cytokines (risk factor), lung damage (mediator), and COVID-19 outcomes.

Immunosuppression with Generics in Liver and Kidney Transplantation: A Real-World Evidence Study.

Purpose: This study evaluates the use, benefit-risk profile, and economic impact of generic immunosuppressants (tacrolimus-TAC, cyclosporine-CsA, and mycophenolate-MYC) in kidney and liver transplant recipients compared to brand-name drugs. Patients and Methods: A retrospective multicentre observational study, involving four Italian regions, was conducted based on the national transplant Information system and regional healthcare claims data. The analysis focused on incident patients who received kidney and liver transplants between 2013 and 2019 and evaluated the use of generic of CsA, TAC, and MYC during the 30-day period following discharge. For each type of transplant and immunosuppressive agent, the benefit-risk profile of generic vs branded drugs in a two-year window was estimated by multivariate Cox models (HR; 95% CI). Furthermore, the potential cost savings per person associated with one year of treatment using generics were calculated. Results: The utilization of generic drugs showed a significant increase; over the study years, the proportion of users among kidney recipients ranged from 14.2% to 40.5% for TAC, from 36.9% to 56.7% for MYC, and from 18.2% to 94.7% for CsA. A great variability in generic uptake for region was found. A comparable risk-benefit profile between generic and branded formulations was shown for all immunosuppressors considered. Choosing generic immunosuppressants during maintenance could result in yearly savings of around 2000 euros per person for each therapy ingredient. Conclusion: The study shows an increasing proportion of patients using generic immunosuppressive drugs over time suggesting a growing acceptance of generics within the transplant community and reveals comparable risk-benefit profiles between the generic and branded formulations of TAC, CsA, and MYC. A significant variability in the use of generics immunosuppressive agents was found both at the regional level and among transplant centers and future research should delve into regional prescribing variations.

Effectiveness and safety of immunosuppressive regimens used as maintenance therapy in kidney transplantation: The CESIT study.

Maintenance immunosuppressive therapy used in kidney transplantation typically involves calcineurin inhibitors, such as tacrolimus or cyclosporine, in combination with mycophenolate or mechanistic target of rapamycin (mTORi) with or without corticosteroids. An Italian retrospective multicentre observational study was conducted to investigate the risk-benefit profile of different immunosuppressive regimens. We identified all subjects who underwent kidney transplant between 2009 and 2019, using healthcare claims data. Patients on cyclosporine and tacrolimus-based therapies were matched 1:1 based on propensity score, and effectiveness and safety outcomes were compared using Cox models (HR; 95%CI). Analyses were also conducted comparing mTORi versus mycophenolate among tacrolimus-treated patients. Patients treated with cyclosporine had a higher risk of rejection or graft loss (HR:1.69; 95%CI:1.16-2.46) and a higher incidence of severe infections (1.25;1.00-1.55), but a lower risk of diabetes (0.66;0.47-0.91) compared to those treated with tacrolimus. Among tacrolimus users, mTORi showed non-inferiority to MMF in terms of mortality (1.01;0.68-1.62), reject/graft loss (0.61;0.36-1.04) and severe infections (0.76;0.56-1.03). In a real-life setting, tacrolimus-based immunosuppressive therapy appeared to be superior to cyclosporine in reducing rejection and severe infections, albeit with an associated increased risk of diabetes. The combination of tacrolimus and mTORi may represent a valid alternative to the combination with mycophenolate, although further studies are needed to confirm this finding.

Post-marketing active surveillance of Guillain Barré Syndrome following COVID-19 vaccination in persons aged ≥12 years in Italy: A multi-database self-controlled case series study.

BACKGROUND: Recently published studies have reported association of COVID-19 vaccine ChAdOx1-S (Vaxzevria) with Guillain Barré Syndrome (GBS). Less is known about the safety of other COVID-19 vaccines with respect to GBS outcome. This study investigated the association of COVID-19 vaccines with GBS in more than 15 million persons aged ≥12 years in Italy. METHODS: Study population was all individuals aged ≥12 years who received at least one dose of COVID-19 vaccines, admitted to emergency care/hospital for GBS from 27 December 2020-30 September 2021 in Italy. Identification of GBS cases and receipt of at least one dose of mRNA-1273 (Elasomeran), BNT162b2 (Tozinameran), ChAdOx1-S (Vaxzevria) and Ad26.COV2.S (Janssen) through record linkage between regional health care and vaccination registries. Relative Incidence (RI) was estimated Self-controlled case series method adapted to event-dependent exposure using in the 42-day exposure risk period after each dose compared with other observation periods. RESULTS: Increased risk of GBS was found after first (RI = 6.83; 95% CI 2.14-21.85) and second dose (RI = 7.41; 2.35-23.38) of mRNA-1273 and first dose of ChAdOx1-S (RI = 6.52; 2.88-14.77). Analysis by age found an increased risk among those aged≥60 years after first (RI = 8.03; 2.08-31.03) and second dose (RI = 7.71; 2.38-24.97) of mRNA-1273. The first dose of ChAdOx1-S was associated with GBS in those aged 40-59 (RI = 4.50; 1.37-14.79) and in those aged ≥ 60 years (RI = 6.84; 2.56-18.28). CONCLUSIONS: mRNA-1273 and ChAdOx1-S vaccines were associated with an increased risk of GBS however this risk resulted in a small number of excess cases. Limitations were loss of GBS outpatient cases and imprecision of the estimates in the subgroup analysis due to a low number of events.

The meaning of dignity in care during the COVID-19 pandemic: a qualitative study in acute and intensive care.

BACKGROUND: The pandemic Era has forced palliative care professionals to use a dignity-in-care approach in different settings from the classic ones of palliative care: acute and intensive care. We explored the meanings of dignity for patients, their family members, and clinicians who have experienced COVID-19 in the acute and intensive care setting. METHODS: A qualitative, prospective study by means of semi-structured interviews with patients hospitalized for COVID-19, family members, and clinicians who care for them. FINDINGS: Between March 2021 and October 2021, we interviewed 16 participants: five physicians, three nurses, and eight patients. None of the patients interviewed consented for family members to participate: they considered it important to protect them from bringing the painful memory back to the period of their hospitalization. Several concepts and themes arose from the interviews: humanity, reciprocity, connectedness, and relationship, as confirmed by the literature. Interestingly, both healthcare professionals and patients expressed the value of informing and being informed about clinical conditions and uncertainties to protect dignity. CONCLUSIONS: Dignity should be enhanced by all healthcare professionals, not only those in palliative care or end-of-life but also in emergency departments.

Determinants of immunosuppressive therapy in renal transplant recipients: an Italian observational study (the CESIT project).

BACKGROUND: Very scanty evidence is available on factors influencing the choice of immunosuppressive drug therapy after kidney transplantation. METHODS: An Italian multiregional real-world study was conducted integrating national transplant information system and claims data. All patients undergoing kidney transplantation for the first time during 2009-2019 (incident patients) were considered. Multilevel logistic models were used to estimate Odds Ratio (OR) and corresponding 95% Confidence intervals. Factors with statistically significance were identified as characteristics associated with treatment regimens: cyclosporin-CsA vs tacrolimus-Tac and, within the latter group, mTOR inhibitors vs mycophenolate-MMF. RESULTS: We identified 3,622 kidney patients undergoing transplantation in 17 hospitals located in 4 Italian regions, 78.3% was treated with TAC-based therapy, of which 78% and 22% in combination with MMF and mTOR, respectively. For both comparison groups, the choice of immunosuppressive regimens was mostly guided by standard hospital practices. Only few recipient and donor characteristics were found associated with specific regimen (donor/receipt age, immunological risk and diabetes). CONCLUSIONS: The choice of post-renal transplant immunosuppressive therapy seems to be mostly driven by standard Centre practices, while only partially based on patient's characteristics and recognized international guidelines.

Postmarketing observational study on the safety of 2021/2022 and 2022/2023 influenza vaccination campaigns in Italy: TheShinISS-Vax|Flu study protocol.

INTRODUCTION: The purpose of TheShinISS-Vax|Flu study is to examine the association between influenza vaccines and adverse events requiring hospital admission or emergency care during the influenza vaccination campaigns 2021/2022 and 2022/2023 in Italy. METHODS AND ANALYSIS: This is a Self-Controlled Case Series multiregional study using linked routinely collected data from regional healthcare databases of the participating regions. Study participants will be persons aged ≥6 months, unvaccinated or who have received influenza vaccine during the influenza vaccination campaigns in the seasons 2021/2022 and 2022/2023 in Italy and who have experienced the outcome of interest for the first time during the study period (1 September 2021-30 June 2022 and 1 September 2022-30 June 2023 for the first and second vaccination campaigns, respectively). Risk periods will be specifically defined for each outcome and further subdivided into periods of 7 days. The exposures will be the first or second dose of the influenza vaccines administered during the two vaccination campaigns. Statistical analysis will be conducted separately for the data of the two campaigns. Exposure risk period will be compared with baseline risk period defined as any time of observation out of the risk periods. The modified SCCS method will be applied to handle event-dependent exposure and mortality and fitted using unbiased estimating equations to estimate relative incidences and excess of cases per 100 000 vaccinated by dose, age, sex and type of vaccine. Calendar period will be included as time-varying confounder in the model, where appropriate. ETHICS AND DISSEMINATION: The study received the approval from the National ethics committee for clinical trials of public research bodies and other national public institutions (PRE BIO CE n.0036723, 23/09/2022). Results will be published in peer-reviewed journals and reports in accordance with the publication policies of the Italian National Institute of Health and of the Italian Medicines Agency.

Case report of Usutu virus infection in an immunocompromised patient in Italy, 2022.

Usutu virus (USUV) is an arthropod-borne flavivirus emerged in Africa in 1950s and in Eruope in 1990s causing a massive number of birds' deaths. The role of USUV as human pathogen has been only recently hypothesized and cases of USUV infection in humans remain limited and often related to immunocompromised subjects. Herein, we report a case of USUV meningoencephalitis infection in an immunocompromised patient with no history of previous flavivirus infection. The infection due to USUV evolved rapidly since hospital admission thus resulting fatal in few days after symptoms onset and, although not proven, a suspected bacteria co-infection has been hypothesized. Based on these findings, we suggested that when USUV meningoencephalitis is suspected in countries endemic, careful attention should be applied to neurological syndromes during summer months especially among immunocompromised patients.

Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.

BACKGROUND & AIMS: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies. METHODS: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed. RESULTS: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function. CONCLUSIONS: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection. IMPACT AND IMPLICATIONS: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models.

Risk of SARS-CoV-2 reinfection by vaccination status, predominant variant and time from prior infection: a cohort study, Reggio Emilia province, Italy, February 2020 to February 2022.

BackgroundUnderstanding the epidemiology of reinfections is crucial for SARS-CoV-2 control over a long period.AimTo evaluate the risk of SARS-CoV-2 reinfection by vaccination status, predominant variant and time after first infection.MethodsWe conducted a cohort study including all residents in the Reggio Emilia province on 31 December 2019, followed up until 28 February 2022 for SARS-CoV-2 first infection and reinfection after 90 days. Cox models were used to compare risk of first infection vs reinfection, adjusting for age, sex, vaccine doses and comorbidities.ResultsThe cohort included 538,516 residents, 121,154 with first SARS-CoV-2 infections and 3,739 reinfections, most in the Omicron BA.1 period. In the pre-Omicron period, three doses of vaccine reduced risk of reinfection by 89% (95% CI: 87-90), prior infection reduced risk by 90% (95% CI: 88-91), while two doses and infection reduced risk by 98% (95% CI: 96-99). In the Omicron BA.1 period, protection estimates were 53% (95% CI: 52-55), 9% (95% CI: 4-14) and 76% (95% CI: 74-77). Before Omicron, protection from reinfection remained above 80% for up to 15 months; with Omicron BA.1, protection decreased from 71% (95% CI: 65-76) at 5 months to 21% (95% CI: 10-30) at 22 months from the first infection. Omicron BA.1 reinfections showed 48% (95% CI: 10-57) lower risk of severe disease than first infections.ConclusionsNatural immunity acquired with previous variants showed low protection against Omicron BA.1. Combined vaccination and natural immunity seems to be more protective against reinfection than either alone. Vaccination of people with prior infection reduced the risk of severe disease.

Profiling the risk of hepatocellular carcinoma after long-term HCV eradication in patients with liver cirrhosis in the PITER cohort.

BACKGROUND AND AIMS: Severe liver disease markers assessed before HCV eradication are acknowledged to usually improve after the SVR. We prospectively evaluated, in the PITER cohort, the long-term HCC risk profile based on predictors monitored after HCV eradication by direct-acting antivirals in patients with cirrhosis. METHODS: HCC occurrence was evaluated by Kaplan-Meier analysis. Cox regression analysis identified the post-treatment variables associated with de-novo HCC; their predictive power was presented in a nomogram. RESULTS: After the end of therapy (median follow-up:28.47 months), among 2064 SVR patients, 119 (5.8%) developed de-novo HCC. The HCC incidence was 1.90%, 4.21%, 6.47% at 12-, 24- and 36-months from end-of-therapy, respectively (incidence rate 2.45/100 person-years). Age, genotype 3, diabetes, platelets (PLT)≤120,000/µl and albumin ≤3.5g/dl levels were identified as pre-treatment HCC independent predictors. Adjusting for age, the post-treatment PLT≤120,000/µl (AdjHR 1.92; 95%CI:1.06-3.45) and albumin≤3.5g/dl (AdjHR 4.38; 95%CI 2.48-7.75) values were independently associated with HCC occurrence. Two different risk profiles were identified by combining long-term post-therapy evaluation of PLT ≤ vs. >120,000/µl and albumin ≤ vs. >3.5g/dl showing a significant different HCC incidence rate of 1.35 vs. 3.77/100 p-y, respectively. CONCLUSIONS: The nomogram score based on age, PLT and albumin levels after SVR showed an accurate prediction capability and may support the customizing management for early HCC detection.

Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro.

OBJECTIVE: Exhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function. DESIGN: HBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients. RESULTS: Severely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2. CONCLUSIONS: The possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.

Active screening of COVID-19-associated pulmonary aspergillosis with serum beta-glucan and endotracheal aspirates galactomannan and fungal culture.

BACKGROUND: Since February 2021 active screening of COVID-19-associated pulmonary aspergillosis (CAPA) has been implemented in our institution. OBJECTIVES: To evaluate CAPA incidence in our centre and evaluate performance of our screening protocol. METHODS: We screened once per week, collecting endotracheal aspirates for fungal culture and galactomannan (GM) and serum for 1,3-ß-D-glucan (BG). In case of positivity (GM more than 4.5, platelia assay, and/or BG >7 pg/ml, wako and/or positive fungal culture), second-level investigations were performed to pursue CAPA diagnosis according to ECMM/ISHAM criteria: bronchoalveolar lavage (BAL) fungal culture and GM, chest computed tomography (CT), serum GM. RESULTS: A total of 102 patients were screened (median age 64 years, range 39-79; 28 (27.4%) females). Twenty-two patients were diagnosed with CAPA (21%). 12 patients were positive for serum BG, 17 patients were positive for endotracheal aspirates GM and 27 patients were positive for endotracheal aspirates fungal culture. Thirty-two BALs were performed, and 26 patients underwent CT chest. Following the second level investigations 61% of the patients with positive screening tests were diagnosed with CAPA. Serum BG above 20 pg/ml or positive serum GM were always associated with typical CT chest signs of aspergillosis. Compared with 1 single positive test, having 2 positive screening test was significantly more associated with CAPA diagnosis (p = .0004). CONCLUSIONS: Active CAPA screening with serum 1,3-ß-D-glucan and endotracheal aspirates galactomannan and fungal cultures and consequent second level investigations led to high number of CAPA diagnosis. Combining more positive fungal biomarkers was more predictive of CAPA diagnosis.

Comparable cytokine release ex-vivo by whole blood from COVID-19 patients with and without non-invasive ventilation.

T cells are key players in the resolution of the infection by SARS-CoV-2. A delay in their activation can lead to severe COVID-19. The present work aimed to identify differences in cytokine release by T cells ex-vivo between COVID-19 patients in the acute phase, showing diverse disease severity. Concentrations of IFNγ, Granzyme B, IL-6, IL-10, IL-17A, IL-18, IP-10, MCP-1, and TNFα were evaluated after stimulation ex-vivo of whole blood samples with peptides from SARS-CoV-2 spike protein and a mitogen as well as without stimulation. Samples derived from hospitalized COVID-19 patients and SARS-CoV-2 vaccinated controls (CTR). Patients were classified on disease severity considering the necessity of non-invasive ventilation (NIV). Samples from patients requiring NIV revealed a similar release of cytokines compared with patients without NIV. COVID-19 patients showed higher spontaneous production of IFNγ and IP-10, lower production of MCP-1 after SARS-CoV-2 peptide stimulation and lower production of IFNγ, IL-10, IL-17A, Granzyme B, IP-10 after mitogenic stimulus compared with CTR. In conclusion, differences in T cell responses evaluated ex-vivo by a whole blood-based cytokine release assay do not appear to explain the need for non-invasive ventilation in COVID-19 patients.

An Italian multicentre distributed data research network to study the use, effectiveness, and safety of immunosuppressive drugs in transplant patients: Framework and perspectives of the CESIT project.

The goal of post-transplant immunosuppressive drug therapy is to prevent organ rejection while minimizing drug toxicities. In clinical practice, a multidrug approach is commonly used and involves drugs with different mechanisms of action, including calcineurin inhibitors (CNI) (tacrolimus or cyclosporine), antimetabolite (antimet) (mycophenolate or azathioprine), inhibitors of mechanistic target of rapamycin (mTOR) (sirolimus or everolimus), and/or steroids. Although evidence based on several randomized clinical trials is available, the optimal immunosuppressive therapy has not been established and may vary among organ transplant settings. To improve the knowledge on this topic, a multiregional research network to Compare the Effectiveness and Safety of Immunosuppressive drugs in Transplant patients (CESIT) has been created with the financial support of the Italian Medicines Agency. In this article, we describe the development of this network, the framework that was designed to perform observational studies, and we also give an overview of the preliminary results that we have obtained. A multi-database transplant cohort was enrolled using a common data model based on healthcare claims data of four Italian regions (Lombardy, Veneto, Lazio, and Sardinia). Analytical datasets were created using an open-source tool for distributed analysis. To link the National Transplant Information System to the regional transplant cohorts, a semi-deterministic record linkage procedure was performed. Overall, 6,914 transplant patients from 2009-19 were identified: 4,029 (58.3%) for kidney, 2,219 (32.1%) for liver, 434 (6.3%) for heart, and 215 (3.1%) for lung. As expected, demographic and clinical characteristics showed considerable variability among organ settings. Although the triple therapy in terms of CNI + antimet/mTOR + steroids was widely dispensed for all settings (63.7% for kidney, 33.5% for liver, 53.3% for heart, and 63.7% for lung), differences in the active agents involved were detected. The CESIT network represents a great opportunity to study several aspects related to the use, safety, and effectiveness of post-transplant maintenance immunosuppressive therapy in real practice.

Modifications of Chest CT Body Composition Parameters at Three and Six Months after Severe COVID-19 Pneumonia: A Retrospective Cohort Study.

We aimed to describe body composition changes up to 6-7 months after severe COVID-19 and to evaluate their association with COVID-19 inflammatory burden, described by the integral of the C-reactive protein (CRP) curve. The pectoral muscle area (PMA) and density (PMD), liver-to-spleen (L/S) ratio, and total, visceral, and intermuscular adipose tissue areas (TAT, VAT, and IMAT) were measured at baseline (T0), 2-3 months (T1), and 6-7 months (T2) follow-up CT scans of severe COVID-19 pneumonia survivors. Among the 208 included patients (mean age 65.6 ± 11 years, 31.3% females), decreases in PMA [mean (95%CI) -1.11 (-1.72; -0.51) cm2] and in body fat areas were observed [-3.13 (-10.79; +4.52) cm2 for TAT], larger from T0 to T1 than from T1 to T2. PMD increased only from T1 to T2 [+3.07 (+2.08; +4.06) HU]. Mean decreases were more evident for VAT [-3.55 (-4.94; -2.17) cm2] and steatosis [L/S ratio increase +0.17 (+0.13; +0.20)] than for TAT. In multivariable models adjusted by age, sex, and baseline TAT, increasing the CRP interval was associated with greater PMA reductions, smaller PMD increases, and greater VAT and steatosis decreases, but it was not associated with TAT decreases. In conclusion, muscle loss and fat loss (more apparent in visceral compartments) continue until 6-7 months after COVID-19. The inflammatory burden is associated with skeletal muscle loss and visceral/liver fat loss.