Publications by authors named "Francesco Castelli"

278 Publications

Interaction of new sigma ligands with biomembrane models evaluated by differential scanning calorimetry and Langmuir-Blodgett studies.

Colloids Surf B Biointerfaces 2021 Feb 18;201:111643. Epub 2021 Feb 18.

Dipartimento di Scienze del Farmaco, Viale Andrea Doria 6, 95125, Catania, Italy. Electronic address:

The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a selective sigma 1 (σ) antagonist with antinociceptive effect, able to increase selective opioid receptor agonist-mediated analgesia. The parent compound (-)-MRV3 [(-)-methyl (1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)-methyl]-1-phenylcyclopropanecarboxylate], a σ antagonist with an improved σ/σ selectivity respect to (+)-MR200, play a role in both central sensitization and pain hypersensitivity, suggesting a potential use of σ antagonists for the treatment of persistent pain conditions. With the intention to assessing the membrane absorption of compounds and their ability to cross it, the interaction of (+)-MR200 and (-)-MRV3 with dimyristoylphosphatidylcholine phospholipids (DMPC), used as biomembrane models was studied by Differential Scanning Calorimetry (DSC) and Langmuir-Blodgett (LB).
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http://dx.doi.org/10.1016/j.colsurfb.2021.111643DOI Listing
February 2021

Lopinavir/ritonavir: Repurposing an old drug for HIV infection in COVID-19 treatment.

Biomed J 2020 Nov 10. Epub 2020 Nov 10.

University Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy. Electronic address:

Currently, there is no specific antiviral treatment for COVID-19. However, drugs previously developed to treat other viral infections are being tested to verify if they might also be effective against SARS-CoV-2, the virus that causes COVID-19. Twenty years ago, the F.D.A. approved Lopinavir/ritonavir (LPV/r) to treat HIV infection. LPV and ritonavir were initially purposed to inhibit 3-chymotrypsin-like protease (3CL) of SARS-CoV and MERS-CoV and preliminary promising data on its efficacy for treating people infected with those viruses were available. Therefore, due to the high genetic similarities among those viruses and SARS-CoV-2, early during COVID-19 pandemic LPV/r was also proposed as one emergency treatment. We reviewed data from the literature about LPV/r treatment and SARS-CoV-2 infection, mainly focused on the efficacy and safety of this drugs for COVID-19 treatment. We can conclude that although up to date no clear benefit has been observed with the LPV/r treatment beyond standard care, its efficacy against SARS-COV-2 infection deserves further evaluations, particularly during the very early phase of the disease.
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http://dx.doi.org/10.1016/j.bj.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654234PMC
November 2020

SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses.

Clin Infect Dis 2021 Jan 4. Epub 2021 Jan 4.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy.

Background: Recent findings indicated that SARS-CoV-2 related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the CSF correlates of SARS-CoV-2 encephalitis.

Methods: Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin).

Results: Thirteen COV-Enc, 21 ENC and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases.

Conclusions: SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.
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http://dx.doi.org/10.1093/cid/ciaa1933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799260PMC
January 2021

High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting.

J Viral Hepat 2021 Mar 2;28(3):558-568. Epub 2021 Jan 2.

U.O. Malattie Infettive e Tropicali, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.
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http://dx.doi.org/10.1111/jvh.13454DOI Listing
March 2021

The importance of SHBG and calculated free testosterone for the diagnosis of symptomatic hypogonadism in HIV-infected men: a single-centre real-life experience.

Infection 2020 Dec 8. Epub 2020 Dec 8.

Department of Clinical and Experimental Sciences, Unit of Endocrinology and Metabolism, University of Brescia, Viale Europa 11, 25123, Brescia, Italy.

Purpose: The prevalence of low testosterone and symptoms of hypogonadism in HIV-infected men is still debated. We aimed to estimate the prevalence and type of hypogonadism in HIV-infected males complaining about sexual symptoms, and to evaluate the role of calculated free testosterone (cFT) vs total testosterone (TT) for diagnosis. Furthermore, we evaluated relationship between sex hormone-binding globulin (SHBG), gonadal status and clinical and virologic parameters.

Methods: We retrospectively evaluated 169 HIV-infected men with sexual symptoms, with TT available. Among them, we selected 94 patients with TT, SHBG, cFT, and luteinizing hormone (LH) available, and classified hypogonadism into overt (low TT and/or low cFT) and compensated (high LH, normal TT and cFT). Comparison was performed by non-parametric Kruskal-Wallis test and Spearman's correlation was calculated to verify the possible associations.

Results: Overt and compensated hypogonadism were found in 20.2% and 13.8% of patients, respectively. With reliance on TT alone, only 10.6% of patients would have met diagnosis. SHBG values were elevated in one third of patients, and higher in men with compensated hypogonadism. Significant positive correlation was found between SHBG and HIV infection duration, TT and LH.

Conclusion: Only a complete hormonal profile can properly diagnose and classify hypogonadism in HIV-infected men complaining about sexual symptoms. TT alone reliance may lead to half of diagnoses missing, while lack of gonadotropin prevents the identification of compensated hypogonadism. This largely comes from high SHBG, which seems to play a central role in the pathogenesis of hypogonadism in this population.
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http://dx.doi.org/10.1007/s15010-020-01558-6DOI Listing
December 2020

Sustainable Development Goals and 2030 Agenda: Awareness, Knowledge and Attitudes in Nine Italian Universities, 2019.

Int J Environ Res Public Health 2020 12 2;17(23). Epub 2020 Dec 2.

Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Puglia, Italy.

Sustainable Development Goals (SDGs) and 2030 Agenda represent global development programs. Education can widen the acknowledgement of their relevance and their applications. This survey aims to assess awareness, knowledge and attitudes towards SDGs and sustainability among first-year students in nine Italian Universities. A Likert scale-based online questionnaire of 70 items was compiled by students from March to July 2019. It examined knowledge and expectations referred to sustainable development concepts, indicators and documents/models accounting for sociodemographic variables. Statistical analyses performed were Chi-square test, Fisher's Exact test, Kendall's W correlation coefficient, univariate and multivariate analysis. The questionnaire was completed by 1676 students. A low percentage referred a good knowledge of SDGs and 2030 Agenda, most of them had never attended related educational activities previously. Better knowledge of SDGs and 2030 Agenda was observed in case of previous specific educational activities ( < 0.001). The expectation towards university guaranteeing an education on SDGs was high, both for personal wisdom and for usefulness in future professional context. A significant difference ( < 0.001) in such expectations was found, as healthcare students were less interested than colleagues of other areas. The results showed low knowledge but interest towards sustainable development. A scheduled implementation of academic initiatives should be considered.
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http://dx.doi.org/10.3390/ijerph17238968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730411PMC
December 2020

Discharge ward during the SARS-CoV-2 pandemic: an effective way to increase patient turnover when human resources are scarce.

Infez Med 2020 Dec;28(4):539-544

Division of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili, Brescia, Italy.

During the SARS-CoV-2 pandemic, the province of Brescia (Italy) had a significant number of COVID-19 cases, which led to a subversion of the ordinary structure of the university hospital ASST Spedali Civili, driven by the need to hospitalize as many patients as possible in a narrow period of time. At the peak of the epidemic, a rapid hospitalization discharge area, the Discharge Ward (DW), was set up with the aim of facilitating the rapid turnover of patients in the wards where the most severe patients had to be hospitalized. The organization and activities carried out are described in the results of this reproducible experience during epidemic events.
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December 2020

An immune-based biomarker signature is associated with mortality in COVID-19 patients.

JCI Insight 2021 01 11;6(1). Epub 2021 Jan 11.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.

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.
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http://dx.doi.org/10.1172/jci.insight.144455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821609PMC
January 2021

Hypogonadism and bone health in men with HIV.

Lancet HIV 2020 11;7(11):e782-e790

Department of Clinical and Experimental Sciences, Unit of Endocrinology and Metabolism, University of Brescia and L'Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy. Electronic address:

The advent of new classes of antiretroviral drugs has improved the survival of people with HIV, and several ageing-related conditions, including hypogonadism and osteoporosis, have emerged. However, both are silent conditions, and are underestimated, underdiagnosed, and not adequately treated. Several factors, including the effects of the virus, antiretroviral therapy, lifestyle factors, and comorbidities, contribute to testicular dysfunction, which in turn has important effects on bone health. The prevalence of hypogonadism is approximately 20% among men with HIV, but extreme variability in the laboratory and clinical assessment of hypogonadism is reported. The prevalence of osteoporosis is 10-30%, but the poor quality of most studies does not allow definitive conclusions on clinical management. Nonetheless, the early and detailed evaluation of gonadal function and bone health is crucial for improving the quality of life of men with HIV.
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http://dx.doi.org/10.1016/S2352-3018(20)30236-8DOI Listing
November 2020

Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial.

J Transl Med 2020 10 21;18(1):405. Epub 2020 Oct 21.

Department of Mental Health and Preventive Medicine, Università degli Studi della Campania Luigi Vanvitelli, Caserta, Italy.

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 < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline.

Conclusions: Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).
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http://dx.doi.org/10.1186/s12967-020-02573-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576974PMC
October 2020

Consequences of the COVID-19 pandemic on the continuum of care in a cohort of people living with HIV followed in a single center of Northern Italy.

AIDS Res Ther 2020 10 4;17(1):59. Epub 2020 Oct 4.

Department of Infectious Diseases, University of Brescia, Brescia, Italy.

Introduction: During the COVID-19 pandemic, hospitals faced increasing pressure, where people living with HIV risked to either acquire SARS-CoV-2 and to interrupt the HIV continuum of care.

Methods: This is a retrospective, observational study. We compared the numbers of medical visits performed, antiretroviral drugs dispensed and the number of new HIV diagnosis and of hospitalizations in a cohort of people living with HIV (PLWH) followed by the Spedali Civili of Brescia between the bimester of the COVID-19 pandemic peak and the bimester of October-November 2019. Data were retrieved from administrative files and from paper and electronic clinical charts. Categorical variables were described using frequencies and percentages, while continuous variables were described using mean, median, and interquartile range (IQR) values. Means for continuous variables were compared using Student's t-tests and the Mann-Whitney test. Proportions for categorical variables were compared using the χ test.

Results: As of December 31st, 2019, a total of 3875 PLWH were followed in our clinic. Mean age was 51.4 ± 13 years old, where 28% were females and 18.8% non-Italian. Overall, 98.9% were on ART (n = 3834), 93% were viro-suppressed. A total of 1217 and 1162 patients had their visit scheduled at our out-patient HIV clinic during the two bimesters of 2019 and 2020, respectively. Comparing the two periods, we observed a raise of missed visits from 5 to 8% (p < 0.01), a reduction in the number of new HIV diagnosis from 6.4 in 2019 to 2.5 per month in 2020 (p = 0.01), a drop in ART dispensation and an increase of hospitalized HIV patients due to COVID-19. ART regimens including protease inhibitors (PIs) had a smaller average drop than ART not including PIs (16.6 vs 21.6%, p < 0.05). Whether this may be due to the perception of a possible efficacy of PIs on COVID19 is not known.

Conclusions: Our experience highlights the importance of a resilient healthcare system and the need to implement new strategies in order to guarantee the continuum of HIV care even in the context of emergency.
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http://dx.doi.org/10.1186/s12981-020-00314-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533114PMC
October 2020

Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study.

J Infect Dis 2021 01;223(1):28-37

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes.

Methods: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded.

Results: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis.

Conclusions: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543535PMC
January 2021

Valacyclovir for cytomegalovirus infection in pregnancy: additional evidences, additional questions.

Clin Microbiol Infect 2020 Sep 17. Epub 2020 Sep 17.

Infectious and Tropical Diseases Unit, Careggi University and Hospital, Florence, Italy; Referral Centre for Infectious Diseases in Pregnancy of Tuscany, Florence, Italy.

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http://dx.doi.org/10.1016/j.cmi.2020.09.015DOI Listing
September 2020

Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia.

Infection 2020 Sep 10. Epub 2020 Sep 10.

University Division of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili Hospital, Brescia, Italy.

Background: SARS-CoV-2 pandemic has posed formidable public health and clinical challenges. The use of immunosuppressive agents, such as high dose corticosteroids and cytokine inhibitors (e.g., Tocilizumab) has been suggested to contrast the hyperinflammatory process involved in the pathogenesis of the severe disease, with conflicting evidence. Among the drawbacks of immunosuppressive therapy, the risk of reactivation of latent infections, including parasitic infestations, is to be considered.

Case Presentation: We report a case of a 59-year-old Italian patient treated with high dose intravenous dexamethasone and two intravenous doses of Tocilizumab for interstitial bilateral pneumonia associated with SARS-CoV-2 infection who developed itching, abdominal pain, and an increased eosinophil count. Stool examination confirmed the presence of S. stercoralis larvae. The patient was treated with a 4-day course of Ivermectin with full recovery.

Discussion: We report the first case of S. stercoralis infection following an 11-day treatment with high-dose steroids and Tocilizumab for severe COVID-19. Clinicians should be aware of the risk of strongyloidiasis as a complication of the treatment for severe COVID-19.
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http://dx.doi.org/10.1007/s15010-020-01522-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481762PMC
September 2020

Efficacy and safety of dalbavancin in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and other infections in a real-life setting: data from an Italian observational multicentric study (DALBITA study).

Expert Rev Anti Infect Ther 2020 12 14;18(12):1271-1279. Epub 2020 Aug 14.

Clinic of Infectious Diseases, San Paolo Hospital, ASST Santi Paolo E Carlo, University of Milan , Milan, Italy.

Objectives: We evaluated the efficacy and safety of dalbavancin in ABSSSI and 'other sites' infections' (OTA).

Methods: Observational study involving 11 Italian hospitals including patients that received ≥1 dose of dalbavancin in 2016-2019. The outcome was end-of-treatment efficacy and safety in ABSSSI and OTA in a real-life setting.

Results: 206 patients enrolled (males 50%, median age 62 [IQR 50-76] years), 60.2% ABSSSI, 39.8% OTA. 69.7% ABSSSI 90.7% OTA (p = 0.003) and 46.3% ABSSSI 37.2% OTA (p = 0.786) received previous and concomitant antibiotics, respectively. 82.5% reached clinical cure . Eleven (5.4%) patients had non-serious adverse events (AE). OTA patients showed longer hospitalization (13.5 days, 5.5-22 3, 0-11.7; p<0.0001) and received longer previous (18 days, 9-30 11, 7-19; p = 0.007)/concomitant antibiotic treatments (21 days, 14-52 11, 8-14; p < 0.0001), compared to ABSSSI. ABSSSI and OTA showed similar efficacy (85.5% 75%, p = 0.459) and safety (no AE: 81.5% 64.3%, p = 0.258); efficacy was independent of previous/concomitant therapies.

Conclusions: Dalbavancin demonstrated a success rate of >80%, with similar efficacy/safety in ABSSSI and off-label indications. The preferential use of dalbavancin as second-line or combination therapy would seem to suggest the need for in-depth studies focused on its off-label use.
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http://dx.doi.org/10.1080/14787210.2020.1798227DOI Listing
December 2020

Travel-related hepatitis E: a two-decade GeoSentinel analysis.

J Travel Med 2020 Nov;27(7)

Department of Global Health, Boston University School of Public Health, Boston, USA.

Background: Hepatitis E virus (HEV) is widely distributed worldwide and is endemic in developing countries. Travel-related HEV infection has been reported at national levels, but global data are missing. Moreover, the global availability of HEV diagnostic testing has not been explored so far. The aim of this study is to describe the epidemiology of HEV infections in returning travellers and availability of HEV diagnostic testing in the GeoSentinel surveillance network.

Methods: This was a multicentre retrospective cross-sectional study. All confirmed and probable HEV travel-related infections reported in the GeoSentinel Network between 1999 and 2018 were evaluated. GeoSentinel sites were asked to complete a survey in 2018 to assess the availability and accessibility of HEV diagnostic procedures (i.e. serology and molecular tests) throughout the study period.

Results: Overall, 165 travel-related HEV infections were reported, mainly since 2010 (60%) and in tourists (50%). Travellers were exposed to hepatitis E in 27 countries; most travellers (62%) were exposed to HEV in South Asia. One patient was pregnant at the time of HEV infection and 14 had a concomitant gastrointestinal infection. No deaths were reported. In the 51% of patients with information available, there was no pre-travel consultation. Among 44 GeoSentinel sites that responded to the survey, 73% have access to HEV serology at a local level, while 55% could perform (at a local or central level) molecular diagnostics.

Conclusion: Reported access to HEV diagnostic testing is suboptimal among sites that responded to the survey; this could negatively affect diagnosing HEV. Pre-travel consultations before travel to South Asia and other low-income and high-prevalence areas with a focus on food and water precautions could be helpful in preventing hepatitis E infection. Improved HEV diagnostic capacity should be implemented to prevent and correctly diagnose travel-related HEV infection.
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http://dx.doi.org/10.1093/jtm/taaa132DOI Listing
November 2020

Impact of the SARS-CoV-2 epidemic on tuberculosis treatment outcome in Northern Italy.

Eur Respir J 2020 10 1;56(4). Epub 2020 Oct 1.

Dept of Infectious and Tropical Diseases, University of Brescia, ASST Spedali Civili, Brescia, Italy.

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http://dx.doi.org/10.1183/13993003.02665-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377210PMC
October 2020

Curcumin Containing PEGylated Solid Lipid Nanoparticles for Systemic Administration: A Preliminary Study.

Molecules 2020 Jun 30;25(13). Epub 2020 Jun 30.

Department of Drug Sciences, University of Catania, Viale Andrea Doria n°6, 95125 Catania, Italy.

Curcumin (CUR) has a wide range of pharmacological properties, including anti-inflammatory and antioxidant activities, and it can be considered a good candidate for the potential treatment of central nervous system (CNS) pathologies, although its use in clinical practice is compromised due to its high lipophilicity. Solid lipid nanoparticles (SLNs) are well-known nanocarriers representing a consolidated approach for the delivery of lipophilic compounds, but their systemic use is limited due their short half-life. The formulation of stealth SLNs (pSLNs) could be a valid strategy to overcome this limit. Curcumin-loaded-pSLNs were prepared by the solvent evaporation method. Formulation was characterized for their mean size, zeta potential, size distribution, and morphology. Drug antioxidant activity was evaluated by Oxygen Radical Absorbance Capacity (ORAC) assay. Finally, the obtained formulations were analyzed in terms of long-term stability. Curcumin-loaded-pSLNs showed good technological parameters with a mean particle size below 200 nm, as confirmed by TEM images, and a zeta potential value around -30 mV, predicting good long-term stability. Differential Scanning Calorimetry (DSC) analysis confirmed that PEG micelles interacted with the SLN surface; this suggests the location of the PEG on the pSLN surface. Therefore, these preliminary studies suggest that the produced formulation could be regarded as a promising carrier for the systemic administration.
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http://dx.doi.org/10.3390/molecules25132991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411787PMC
June 2020

Comparing SARS-CoV-2 with SARS-CoV and influenza pandemics.

Lancet Infect Dis 2020 09 3;20(9):e238-e244. Epub 2020 Jul 3.

Department of Science and Environment, Roskilde University, Roskilde, Denmark; Department of Global Health, George Washington University, Washington, DC, USA.

The objective of this Personal View is to compare transmissibility, hospitalisation, and mortality rates for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with those of other epidemic coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and pandemic influenza viruses. The basic reproductive rate (R) for SARS-CoV-2 is estimated to be 2·5 (range 1·8-3·6) compared with 2·0-3·0 for SARS-CoV and the 1918 influenza pandemic, 0·9 for MERS-CoV, and 1·5 for the 2009 influenza pandemic. SARS-CoV-2 causes mild or asymptomatic disease in most cases; however, severe to critical illness occurs in a small proportion of infected individuals, with the highest rate seen in people older than 70 years. The measured case fatality rate varies between countries, probably because of differences in testing strategies. Population-based mortality estimates vary widely across Europe, ranging from zero to high. Numbers from the first affected region in Italy, Lombardy, show an all age mortality rate of 154 per 100 000 population. Differences are most likely due to varying demographic structures, among other factors. However, this new virus has a focal dissemination; therefore, some areas have a higher disease burden and are affected more than others for reasons that are still not understood. Nevertheless, early introduction of strict physical distancing and hygiene measures have proven effective in sharply reducing R and associated mortality and could in part explain the geographical differences.
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http://dx.doi.org/10.1016/S1473-3099(20)30484-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333991PMC
September 2020

Flow Cytometry Identifies Risk Factors and Dynamic Changes in Patients with COVID-19.

J Clin Immunol 2020 10 27;40(7):970-973. Epub 2020 Jun 27.

Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy.

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http://dx.doi.org/10.1007/s10875-020-00806-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320913PMC
October 2020

Laboratory considerations amidst the coronavirus disease 2019 outbreak: the Spedali Civili in Brescia experience.

Bioanalysis 2020 Sep 23;12(17):1223-1230. Epub 2020 Jun 23.

Department of Economics & Management, University of Brescia, Brescia, Italy.

Coronavirus disease 2019 emergency has created an enormous stress on providers that have been transformed into coronavirus disease hospitals. This article presents the experience of the clinical laboratory of Spedali Civili in Brescia (a teaching hospital in Lombardy with over 1500 beds) in managing the crisis, and to offer practical considerations for laboratory testing for this cohort of patients. Our contribution is threefold: by comparing the demand for tests in two representative period before and within the crisis, we show the change in compositions of the analytes that other labs may expect; we present the new panels of tests that hospital staff can order with different advantage for wards and laboratory; and we show how to reorganize staff on the basis of changes mentioned above.
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http://dx.doi.org/10.4155/bio-2020-0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315825PMC
September 2020

Factors associated with immunosenescence during early adulthood in HIV-infected patients after durable efficient combination antiretroviral therapy.

Sci Rep 2020 06 22;10(1):10057. Epub 2020 Jun 22.

Centro di Ricerca Emato-oncologica AIL (CREA), Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy.

Perinatally HIV-infected patients face the consequences of both chronic infection effects per se and long-term combination antiretroviral therapy (cART) on immunosenescence. Aims of our study were to evaluate which factors independently contribute to immunosenescence in HIV-infected young adults with a very different HIV infection duration (perinatally HIV-infected young individuals -pHIVy- and age-matched non perinatally HIV-infected youths -npHIVy), after durable  efficient cART. We considered low thymic and bone marrow output, respectively evaluated by quantifying T-cell receptor excision circles (TRECs), K-deleting recombination excision circles (KRECs), and shorter telomeres lenght (TL) as surrogate biomarkers of immunosenescence. Twenty-one pHIVy and 19 npHIVy (with a mean HIV duration of 3-8 years) were included; mean age was 27 years for both groups. Immunosenescence biomarkers were comparable between pHIVy and npHIVy (despite longer HIV-infection, higher frequency of AIDS events, past cART-free periods and concomitant chronic viral infections in pHIVy). At the multivariate analysis, CD4+ was the only variable independently associated with TRECs and TL. Our data suggest that a good level of thymic activity can compensate the deleterious effects of past periods without cART, if HIV replication is suppressed for a sufficient time.
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http://dx.doi.org/10.1038/s41598-020-67100-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308364PMC
June 2020

SARS-CoV-2 pandemic in the western world: the lessons learned.

J R Coll Physicians Edinb 2020 06;50(2):110-111

University of Brescia, Italy, Email:

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http://dx.doi.org/10.4997/JRCPE.2020.205DOI Listing
June 2020

Factors Associated With Surgical Mortality and Complications Among Patients With and Without Coronavirus Disease 2019 (COVID-19) in Italy.

JAMA Surg 2020 Jun 12. Epub 2020 Jun 12.

Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia and Spedali Civili Hospital, Brescia, Italy.

Importance: There are limited data on mortality and complications rates in patients with coronavirus disease 2019 (COVID-19) who undergo surgery.

Objective: To evaluate early surgical outcomes of patients with COVID-19 in different subspecialties.

Design, Setting, And Participants: This matched cohort study conducted in the general, vascular and thoracic surgery, orthopedic, and neurosurgery units of Spedali Civili Hospital (Brescia, Italy) included patients who underwent surgical treatment from February 23 to April 1, 2020, and had positive test results for COVID-19 either before or within 1 week after surgery. Gynecological and minor surgical procedures were excluded. Patients with COVID-19 were matched with patients without COVID-19 with a 1:2 ratio for sex, age group, American Society of Anesthesiologists score, and comorbidities recorded in the surgical risk calculator of the American College of Surgeons National Surgical Quality Improvement Program. Patients older than 65 years were also matched for the Clinical Frailty Scale score.

Exposures: Patients with positive results for COVID-19 and undergoing surgery vs matched surgical patients without infection. Screening for COVID-19 was performed with reverse transcriptase-polymerase chain reaction assay in nasopharyngeal swabs, chest radiography, and/or computed tomography. Diagnosis of COVID-19 was based on positivity of at least 1 of these investigations.

Main Outcomes And Measures: The primary end point was early surgical mortality and complications in patients with COVID-19; secondary end points were the modeling of complications to determine the importance of COVID-19 compared with other surgical risk factors.

Results: Of 41 patients (of 333 who underwent operation during the same period) who underwent mainly urgent surgery, 33 (80.5%) had positive results for COVID-19 preoperatively and 8 (19.5%) had positive results within 5 days from surgery. Of the 123 patients of the combined cohorts (78 women [63.4%]; mean [SD] age, 76.6 [14.4] years), 30-day mortality was significantly higher for those with COVID-19 compared with control patients without COVID-19 (odds ratio [OR], 9.5; 95% CI, 1.77-96.53). Complications were also significantly higher (OR, 4.98; 95% CI, 1.81-16.07); pulmonary complications were the most common (OR, 35.62; 95% CI, 9.34-205.55), but thrombotic complications were also significantly associated with COVID-19 (OR, 13.2; 95% CI, 1.48-∞). Different models (cumulative link model and classification tree) identified COVID-19 as the main variable associated with complications.

Conclusions And Relevance: In this matched cohort study, surgical mortality and complications were higher in patients with COVID-19 compared with patients without COVID-19. These data suggest that, whenever possible, surgery should be postponed in patients with COVID-19.
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http://dx.doi.org/10.1001/jamasurg.2020.2713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439107PMC
June 2020

Abacavir adverse reactions related with HLA-B*57: 01 haplotype in a large cohort of patients infected with HIV.

Pharmacogenet Genomics 2020 10;30(8):167-174

Department of Infectious and Tropical Diseases, University of Brescia.

Objective: Carriage of human leukocyte antigen (HLA)-B*57:01 allele increases the risk of abacavir hypersensitivity reaction. Therefore, since 2008 HIV treatment guidelines recommend HLA-B*57:01 screening before abacavir administration, greatly reducing hypersensitivity reaction rate. However, clinically suspected abacavir-related hypersensitivity reactions are described in allele non-carriers. Major aim of this study was to evaluate the relationship between HLA-B*57:01 pattern and abacavir-related hypersensitivity reaction, focusing on hypersensitivity reaction prevalence in allele non-carriers.

Methods: We included all outpatients aged >18 years old with HIV infection and known HLA-B*57:01 pattern, followed at our Department from January 2000 until December 2017. Patients were divided according to HLA-B*57:01 pattern and first antiretroviral treatment prescribed (containing or not abacavir) as follows: HLA-B*57:01 allele carriers treated with abacavir and HLA-B*57:01 allele non-carriers treated with abacavir. We considered all adverse events reported during first abacavir administration, differentiating between confirmed hypersensitivity reactions and non-hypersensitivity reactions, according to abacavir hypersensitivity reaction definition included in the abacavir EU Summary of Product Characteristics and the US Prescribing Information.

Results: A total of 3144 patients had a known HLA-B*57:01 pattern. About 5.4% of them showed allele polymorphism; Caucasian ethnicity was the most represented. In this cohort, 1801 patients were treated with a first abacavir-containing regimen (98.2% of them was represented by allele non-carriers). 191 out of 1801 patients discontinued abacavir because of toxicity/intolerance; among them 107 described adverse events fulfilled the criteria of confirmed abacavir hypersensitivity reaction (22/32 allele-positive patients and 85/1769 allele-negative patients). After having experienced a confirmed abacavir hypersensitivity reaction, abacavir was re-administered to eight HLA-B*57:01 negative patients. Seven of them re-experienced a syndrome consistent with hypersensitivity reaction, finally leading to drug discontinuation. Overall, no fatal reactions were described.

Conclusion: Not all abacavir-related side effects occur as a result of classic HLA-B*57:01-mediated hypersensitivity reaction, as they can develop irrespective of HLA-B*57:01 status. Clinical vigilance must be an essential part of the management of individuals starting abacavir, at any time during treatment. In a 'real-life' setting, clinical diagnosis of suspected abacavir hypersensitivity reaction in allele non-carriers remains crucial for further clinical decision making.
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http://dx.doi.org/10.1097/FPC.0000000000000409DOI Listing
October 2020

Steroid-Responsive Encephalitis in Coronavirus Disease 2019.

Ann Neurol 2020 08 9;88(2):423-427. Epub 2020 Jun 9.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Coronavirus disease 2019 (COVID-19) infection has the potential for targeting the central nervous system, and several neurological symptoms have been described in patients with severe respiratory distress. Here, we described the case of a 60-year-old patient with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but only mild respiratory abnormalities who developed an akinetic mutism attributable to encephalitis. Magnetic resonance imaging was negative, whereas electroencephalography showed generalized theta slowing. Cerebrospinal fluid analyses during the acute stage were negative for SARS-CoV-2, positive for pleocytosis and hyperproteinorrachia, and showed increased interleukin-8 and tumor necrosis factor-α concentrations. Other infectious or autoimmune disorders were excluded. A progressive clinical improvement along with a reduction of cerebrospinal fluid parameters was observed after high-dose steroid treatment, thus arguing for an inflammatory-mediated brain involvement related to COVID-19. ANN NEUROL 2020;88:423-427.
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http://dx.doi.org/10.1002/ana.25783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276848PMC
August 2020

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy.

Autoimmun Rev 2020 Jul 3;19(7):102568. Epub 2020 May 3.

University Division of Anesthesiology and Critical Care Medicine, ASST Spedali Civili, Brescia, Italy; Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. Electronic address:

A hyperinflammatory syndrome (HIS) may cause a life-threatening acute respiratory distress syndrome (ARDS) in patients with COVID-19 pneumonia. A prospective series of 100 consecutive patients admitted to the Spedali Civili University Hospital in Brescia (Italy) between March 9th and March 20th with confirmed COVID-19 pneumonia and ARDS requiring ventilatory support was analyzed to determine whether intravenous administration of tocilizumab (TCZ), a monoclonal antibody that targets the interleukin 6 (IL-6) receptor, was associated with improved outcome. Tocilizumab was administered at a dosage of 8 mg/kg by two consecutive intravenous infusions 12 h apart. A third infusion was optional based on clinical response. The outcome measure was an improvement in acute respiratory failure assessed by means of the Brescia COVID Respiratory Severity Score (BCRSS 0 to 8, with higher scores indicating higher severity) at 24-72 h and 10 days after tocilizumab administration. Out of 100 treated patients (88 M, 12 F; median age: 62 years), 43 received TCZ in the intensive care unit (ICU), while 57 in the general ward as no ICU beds were available. Of these 57 patients, 37 (65%) improved and suspended noninvasive ventilation (NIV) (median BCRSS: 1 [IQR 0-2]), 7 (12%) patients remained stable in NIV, and 13 (23%) patients worsened (10 died, 3 were admitted to ICU). Of the 43 patients treated in the ICU, 32 (74%) improved (17 of them were taken off the ventilator and were discharged to the ward), 1 (2%) remained stable (BCRSS: 5) and 10 (24%) died (all of them had BCRSS≥7 before TCZ). Overall at 10 days, the respiratory condition was improved or stabilized in 77 (77%) patients, of whom 61 showed a significant clearing of diffuse bilateral opacities on chest x-ray and 15 were discharged from the hospital. Respiratory condition worsened in 23 (23%) patients, of whom 20 (20%) died. All the patients presented with lymphopenia and high levels of C-reactive protein (CRP), fibrinogen, ferritin and IL-6 indicating a HIS. During the 10-day follow-up, three cases of severe adverse events were recorded: two patients developed septic shock and died, one had gastrointestinal perforation requiring urgent surgery and was alive at day 10. In conclusion, our series showed that COVID-19 pneumonia with ARDS was characterized by HIS. The response to TCZ was rapid, sustained, and associated with significant clinical improvement.
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http://dx.doi.org/10.1016/j.autrev.2020.102568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252115PMC
July 2020

Clinical presentation and initial management critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brescia, Italy.

J Crit Care 2020 08 14;58:29-33. Epub 2020 Apr 14.

Brescia University, Italy. Electronic address:

Purpose: An ongoing pandemic of COVID-19 that started in Hubei, China has resulted in massive strain on the healthcare infrastructure in Lombardy, Italy. The management of these patients is still evolving.

Materials And Methods: This is a single-center observational cohort study of critically ill patients infected with COVID-19. Bedside clinicians abstracted daily patient data on history, treatment, and short-term course. We describe management and a proposed severity scale for treatment used in this hospital.

Results: 44 patients were enrolled; with incomplete information on 11. Of the 33 studied patients, 91% were male, median age 64; 88% were overweight or obese. 45% were hypertensive, 12% had been taking an ACE-inhibitor. Noninvasive ventilation was performed on 39% of patients for part or all or their ICU stay with no provider infection. Most patients received antibiotics for pneumonia. Patients also received lopinivir/ritonavir (82%), hydroxychloroquine (79%), and tocilizumab (12%) according to this treatment algorithm. Nine of 10 patients survived their ICU course and were transferred to the floor, with one dying in the ICU.

Conclusions: ICU patients with COVID-19 frequently have hypertension. Many could be managed with noninvasive ventilation, despite the risk of aerosolization. The use of a severity scale augmented clinician management.
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http://dx.doi.org/10.1016/j.jcrc.2020.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194649PMC
August 2020

Management of Patients on Dialysis and With Kidney Transplantation During the SARS-CoV-2 (COVID-19) Pandemic in Brescia, Italy.

Kidney Int Rep 2020 May 4;5(5):580-585. Epub 2020 Apr 4.

Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease (COVID-19), is a major pandemic challenging health care systems around the world. The optimal management of patients infected with COVID-19 is still unclear, although the consensus is moving toward the need of a biphasic approach. During the first phase of the disease (from onset of the symptoms up to 7-10 days) viral-induced effects are prominent, with the opportunity to institute antiviral therapy. In the second inflammatory phase of the disease, immunosuppressive strategies (for example with glucocorticoids or anticytokine drugs) may be considered. This latter stage is characterized by the development of progressive lung involvement with increasing oxygen requirements and occasionally signs of the hemophagocytic syndrome. The management of the disease in patients with kidney disease is even more challenging, especially in those who are immunosuppressed or with severe comorbidities. Here we present the therapeutic approach used in Brescia (Italy) for managing patients infected with COVID-19 who underwent kidney transplantation and are receiving hemodialysis. Furthermore, we provide some clinical and physiopathological background, as well as preliminary outcome data of our cohort, to better clarify the pathogenesis of the disease and clinical management.
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http://dx.doi.org/10.1016/j.ekir.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128395PMC
May 2020