Publications by authors named "Raffaele Bruno"

168 Publications

Italian association for the study of the liver position statement on SARS-CoV2 vaccination.

Dig Liver Dis 2021 Apr 5. Epub 2021 Apr 5.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy; Humanitas Research Hospital IRCCS, Rozzano, Italy.

The vaccination campaign against Sars-CoV-2 commenced in Italy at the end of December 2020. The first ones to receive the immunization against the virus were the health workers and the residents of nursing homes, following which the vaccine would be available for the entire population, beginning with the most vulnerable individuals. SARS-CoV2 vaccines have been demonstrated to be safe for the general population, although no data for patients with liver diseases or those having undergone liver transplantation are available so far. The present position statement AISF is an attempt to suggest, based on the published data on the impact of Sars-Cov-2 infection in patients with chronic liver disease, a possible priority for vaccination for this category of patients.
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http://dx.doi.org/10.1016/j.dld.2021.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086184PMC
April 2021

Can Alveolar-Arterial Difference and Lung Ultrasound Help the Clinical Decision Making in Patients with COVID-19?

Diagnostics (Basel) 2021 Apr 23;11(5). Epub 2021 Apr 23.

Emergency Medicine Unit and Emergency Medicine Postgraduate Training Program, Department of Internal Medicine, University of Pavia, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy.

Background: COVID-19 is an emerging infectious disease, that is heavily challenging health systems worldwide. Admission Arterial Blood Gas (ABG) and Lung Ultrasound (LUS) can be of great help in clinical decision making, especially during the current pandemic and the consequent overcrowding of the Emergency Department (ED). The aim of the study was to demonstrate the capability of alveolar-to-arterial oxygen difference (AaDO) in predicting the need for subsequent oxygen support and survival in patients with COVID-19 infection, especially in the presence of baseline normal PaO/FiO ratio (P/F) values.

Methods: A cohort of 223 swab-confirmed COVID-19 patients underwent clinical evaluation, blood tests, ABG and LUS in the ED. LUS score was derived from 12 ultrasound lung windows. AaDO was derived as AaDO = ((FiO) (Atmospheric pressure - HO pressure) - (PaCO/R)) - PaO. Endpoints were subsequent oxygen support need and survival.

Results: A close relationship between AaDO and P/F and between AaDO and LUS score was observed (R = 0.88 and R = 0.67, respectively; < 0.001 for both). In the subgroup of patients with P/F between 300 and 400, 94.7% ( = 107) had high AaDO values, and 51.4% ( = 55) received oxygen support, with 2 ICU admissions and 10 deaths. According to ROC analysis, AaDO > 39.4 had 83.6% sensitivity and 90.5% specificity (AUC 0.936; < 0.001) in predicting subsequent oxygen support, whereas a LUS score > 6 showed 89.7% sensitivity and 75.0% specificity (AUC 0.896; < 0.001). Kaplan-Meier curves showed different mortality in the AaDO subgroups ( = 0.0025).

Conclusions: LUS and AaDO are easy and effective tools, which allow bedside risk stratification in patients with COVID-19, especially when P/F values, signs, and symptoms are not indicative of severe lung dysfunction.
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http://dx.doi.org/10.3390/diagnostics11050761DOI Listing
April 2021

Modeling vaccination rollouts, SARS-CoV-2 variants and the requirement for non-pharmaceutical interventions in Italy.

Nat Med 2021 Apr 16. Epub 2021 Apr 16.

Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Despite progress in clinical care for patients with coronavirus disease 2019 (COVID-19), population-wide interventions are still crucial to manage the pandemic, which has been aggravated by the emergence of new, highly transmissible variants. In this study, we combined the SIDARTHE model, which predicts the spread of SARS-CoV-2 infections, with a new data-based model that projects new cases onto casualties and healthcare system costs. Based on the Italian case study, we outline several scenarios: mass vaccination campaigns with different paces, different transmission rates due to new variants and different enforced countermeasures, including the alternation of opening and closure phases. Our results demonstrate that non-pharmaceutical interventions (NPIs) have a higher effect on the epidemic evolution than vaccination alone, advocating for the need to keep NPIs in place during the first phase of the vaccination campaign. Our model predicts that, from April 2021 to January 2022, in a scenario with no vaccine rollout and weak NPIs ([Formula: see text] = 1.27), as many as 298,000 deaths associated with COVID-19 could occur. However, fast vaccination rollouts could reduce mortality to as few as 51,000 deaths. Implementation of restrictive NPIs ([Formula: see text] = 0.9) could reduce COVID-19 deaths to 30,000 without vaccinating the population and to 18,000 with a fast rollout of vaccines. We also show that, if intermittent open-close strategies are adopted, implementing a closing phase first could reduce deaths (from 47,000 to 27,000 with slow vaccine rollout) and healthcare system costs, without substantive aggravation of socioeconomic losses.
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http://dx.doi.org/10.1038/s41591-021-01334-5DOI Listing
April 2021

SARS-CoV-2 specific T-cell immunity in COVID-19 convalescent patients and unexposed controls measured by ex vivo ELISpot assay.

Clin Microbiol Infect 2021 Apr 2. Epub 2021 Apr 2.

Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy.

Objectives: SARS-CoV-2 T-cell response characterization represents a crucial issue for defining the role of immune protection against COVID-19. The aim of the study was to assess the SARS-CoV-2 T-cell response in a cohort of COVID-19 convalescent patients and in a group of unexposed subjects.

Methods: SARS-CoV-2 T-cell response was quantified from peripheral blood mononuclear cells (PBMCs) of 87 COVID-19 convalescent subjects (range 7-239 days after symptom onset) and 33 unexposed donors by ex vivo ELISpot assay. Follow-up of SARS-CoV-2 T-cell response was performed in ten subjects up to 12 months after symptom onset. The role of SARS-CoV-2 specific CD4 and CD8 T cells was characterized in a group of COVID-19 convalescent subjects. Moreover, neutralizing antibodies were determined in serum samples.

Results: In 14/33 (42.4%) unexposed donors and 85/87 (97.7%) COVID-19 convalescent subjects a positive result for at least one SARS-CoV-2 antigen was observed. A positive response was observed up to 12 months after COVID-19 infection (median 246 days after symptom onset; range 118-362 days). Of note, SARS-CoV-2 T-cell response seems to be mainly mediated by CD4 T cells. A weak positive correlation was observed between Spike-specific T-cell response and neutralizing antibody titre (p 0.0028; r = 0.2891) and positive SARS-CoV-2 T-cell response was observed in 8/9 (88.9%) COVID-19 convalescent subjects with undetectable SARS-CoV-2 neutralizing antibodies.

Discussion: Cross-reactive SARS-CoV-2 T-cell response in uninfected patients may be due to previous infections with other common coronaviruses. Our data suggest that long-term SARS-CoV-2 T-cell response might accompany a waning humoral response.
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http://dx.doi.org/10.1016/j.cmi.2021.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016542PMC
April 2021

A case of Corynebacterium striatum endocarditis successfully treated with an early switch to oral antimicrobial therapy.

Infez Med 2021 Mar;29(1):138-144

Division of Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Patients with Corynebacterium striatum endocarditis are usually managed with long-term intravenous antibiotic therapy and hospitalization. Here we describe a case of a 76-year-old woman with hepatitis C virus (HCV) related cirrhosis who developed endocarditis due to Corynebacterium striatum associated with severe aortic regurgitation. To our knowledge, this is the first case to be successfully treated with an early switch to oral linezolid after three weeks of vancomycin. We performed a literature review using the PubMed database and found 27 cases which showed the enhanced virulence of this pathogen especially for long-term hospitalized patients with a frequent need of surgical treatment (44.4%) and long course of parenteral antimicrobial therapy, with vancomycin as drug of choice. There are no studies confirming the possibility of using oral treatment in non-diphtheritic Corynebacteria infective endocarditis. This case report provides us with the evidence that once the patient is in a stable condition, the efficacy and safety of linezolid might be similar to vancomycin administration. New trials and prospective studies are needed to confirm the opportunity of an early switch to oral therapy in this specific setting.
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March 2021

Lung ultrasound presentation of COVID-19 patients: phenotypes and correlations.

Intern Emerg Med 2021 Mar 1. Epub 2021 Mar 1.

Emergency Medicine Unit and Emergency Medicine Postgraduate Training Program, Internal Medicine, Vascular and Metabolic Disease Unit, Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, P.Le Golgi, 19, 27100, Pavia, Italy.

Bedside lung ultrasound (LUS) can play a role in the setting of the SarsCoV2 pneumonia pandemic. To evaluate the clinical and LUS features of COVID-19 in the ED and their potential prognostic role, a cohort of laboratory-confirmed COVID-19 patients underwent LUS upon admission in the ED. LUS score was derived from 12 fields. A prevalent LUS pattern was assigned depending on the presence of interstitial syndrome only (Interstitial Pattern), or evidence of subpleural consolidations in at least two fields (Consolidation Pattern). The endpoint was 30-day mortality. The relationship between hemogasanalysis parameters and LUS score was also evaluated. Out of 312 patients, only 36 (11.5%) did not present lung involvment, as defined by LUS score < 1. The majority of patients were admitted either in a general ward (53.8%) or in intensive care unit (9.6%), whereas 106 patients (33.9%) were discharged from the ED. In-hospital mortality was 25.3%, and 30-day survival was 67.6%. A LUS score > 13 had a 77.2% sensitivity and a 71.5% specificity (AUC 0.814; p < 0.001) in predicting mortality. LUS alterations were more frequent (64%) in the posterior lower fields. LUS score was related with P/F (R 0.68; p < 0.0001) and P/F at FiO = 21% (R 0.59; p < 0.0001). The correlation between LUS score and P/F was not influenced by the prevalent ultrasound pattern. LUS represents an effective tool in both defining diagnosis and stratifying prognosis of COVID-19 pneumonia. The correlation between LUS and hemogasanalysis parameters underscores its role in evaluating lung structure and function.
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http://dx.doi.org/10.1007/s11739-020-02620-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917171PMC
March 2021

Predictors of starting antimicrobial treatment in patients with nontuberculous mycobacterial lung disease in the Italian scenario: A SITA GIOVANI-IRENE promoted web-survey.

Respir Med 2021 04 15;179:106341. Epub 2021 Feb 15.

Infectious Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy; Departement of Pathophysiology and Transplantation, University of Milano, Milano, Italy; Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy.

The disease burden due to nontuberculous mycobacteria is growing worldwide, consequently to improved diagnostic abilities and an increase in the individuals at risk. Uncertainties exist about the right moment on which start treatment. We investigated the clinical features associated with starting an antimicrobial treatment in patients with nontuberculous mycobacterial lung disease among Italian physicians involved in the field. We found that in real life predictors of starting antimicrobial treatment are quite adherent to international guidelines, with some uncertainties regarding the implication of immunosuppressive drugs.
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http://dx.doi.org/10.1016/j.rmed.2021.106341DOI Listing
April 2021

Risk of reactivation of occult hepatitis B during immunotherapy in cancer treatment: myth, reality or new horizons?

Future Oncol 2021 May 16;17(13):1577-1580. Epub 2021 Feb 16.

Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, Pavia, Italy.

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http://dx.doi.org/10.2217/fon-2020-1196DOI Listing
May 2021

Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection.

Med (N Y) 2021 Mar 10;2(3):281-295.e4. Epub 2021 Feb 10.

Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden.

Background: Monitoring the adaptive immune responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection provides useful information for the development of vaccination strategies against this virus and its emerging variants. We thus profiled the serum anti-SARS-CoV-2 antibody (Ab) levels and specific memory B and T cell responses in convalescent coronavirus disease 2019 (COVID-19) patients.

Methods: A total of 119 samples from 88 convalescent donors who experienced mild to critical disease were tested for the presence of elevated anti-spike and anti-receptor binding domain Ab levels over a period of 8 months. In addition, the levels of SARS-CoV-2 neutralizing Abs and specific memory B and T cell responses were tested in a subset of samples.

Findings: Anti-SARS-CoV-2 Abs were present in 85% of the samples collected within 4 weeks after the onset of symptoms in COVID-19 patients. Levels of specific immunoglobulin M (IgM)/IgA Abs declined after 1 month, while levels of specific IgG Abs and plasma neutralizing activities remained relatively stable up to 6 months after diagnosis. Anti-SARS-CoV-2 IgG Abs were still present, although at a significantly lower level, in 80% of the samples collected at 6-8 months after symptom onset. SARS-CoV-2-specific memory B and T cell responses developed with time and were persistent in all of the patients followed up for 6-8 months.

Conclusions: Our data suggest that protective adaptive immunity following natural infection of SARS-CoV-2 may persist for at least 6-8 months, regardless of disease severity. Development of medium- or long-term protective immunity through vaccination may thus be possible.

Funding: This project was supported by the European Union's Horizon 2020 research and innovation programme (ATAC, no. 101003650), the Italian Ministry of Health (Ricerca Finalizzata grant no. GR-2013-02358399), the Center for Innovative Medicine, and the Swedish Research Council. J.A. was supported by the SciLifeLab/KAW national COVID-19 research program project grant 2020.
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http://dx.doi.org/10.1016/j.medj.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874960PMC
March 2021

Dynamic angiopoietin-2 assessment predicts survival and chronic course in hospitalized patients with COVID-19.

Blood Adv 2021 02;5(3):662-673

Internal and Emergency Medicine, Ospedale Civile Baggiovara-Azienda Ospedaliero-Universitaria Modena, Modena, Italy.

This study examined the association between dynamic angiopoietin-2 assessment and COVID-19 short- and long-term clinical course. We included consecutive hospitalized patients from 1 February to 31 May 2020 with laboratory-confirmed COVID-19 from 2 Italian tertiary referral centers (derivation cohort, n = 187 patients; validation cohort, n = 62 patients). Serum biomarker levels were measured by sandwich enzyme-linked immunosorbent assay. Lung tissue from 9 patients was stained for angiopoietin-2, Tie2, CD68, and CD34. Cox model was used to identify risk factors for mortality and nonresolving pulmonary condition. Area under the receiver operating characteristic curve (AUROC) was used to assess the accuracy of 3- and 10-day angiopoietin-2 for in-hospital mortality and nonresolving pulmonary condition, respectively. Three-day angiopoietin-2 increase of at least twofold from baseline was significantly associated with in-hospital mortality by multivariate analysis (hazard ratio [HR], 6.69; 95% confidence interval [CI], 1.85-24.19; P = .004) with AUROC = 0.845 (95% CI, 0.725-0.940). Ten-day angiopoietin-2 of at least twofold from baseline was instead significantly associated with nonresolving pulmonary condition by multivariate analysis (HR, 5.33; 95% CI, 1.34-11.77; P ≤ .0001) with AUROC = 0.969 (95% CI, 0.919-1.000). Patients with persistent elevation of 10-day angiopoietin-2 levels showed severe reticular interstitial thickening and fibrous changes on follow-up computed tomography scans. Angiopoietin-2 and Tie2 were diffusely colocalized in small-vessel endothelia and alveolar new vessels and macrophages. Angiopoietin-2 course is strongly associated with COVID-19 in-hospital mortality and nonresolving pulmonary condition. Angiopoietin-2 may be an early and useful predictor of COVID-19 clinical course, and it could be a relevant part of disease pathogenesis. Angiopoietin-2 blockade may be a COVID-19 treatment option.
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http://dx.doi.org/10.1182/bloodadvances.2020003736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876870PMC
February 2021

Cerebral Toxocariasis as a Cause of Epilepsy: A Pediatric Case.

Neuropediatrics 2021 04 20;52(2):142-145. Epub 2021 Jan 20.

Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Toxocarosis is the consequence of human infection by spp. larvae and is one of the most common ascarioses, not only in developing countries, but also in the European region, where its prevalence reaches 14%. Due to their particular behavior, children are at higher risk of this parasitic infection, whose clinical features depend on the localization of the larvae. Neurotoxocariasis is very uncommon in children and may take different forms depending on the underlying physiopathologic process: immune reaction against the parasite antigens, vasculitis, treatment complications, or, very rarely, brain localization of spp. larvae. The association between neurotoxocariasis and the onset of childhood epilepsy has been postulated but is still debated. Moreover, a spp. abscess causing epileptic seizures in children has been rarely described, especially in western countries. Hereby we present a 9-year-old patient with a new diagnosis of epilepsy definitely secondary to brain abscess due to the localization of larvae. Diagnosis was confirmed by neuroimaging and serological test. The successful treatment with albendazole and steroids was documented with a close and long-term clinical and neuroradiological follow-up. Our experience confirms that every case of cryptogenetic epilepsy in children deserves a neuroimaging study and, in case of cystic images, serology is mandatory to avoid further unnecessary invasive diagnostic investigations and to set the specific drug therapy.
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http://dx.doi.org/10.1055/s-0040-1721701DOI Listing
April 2021

Predicting in-hospital mortality from Coronavirus Disease 2019: A simple validated app for clinical use.

PLoS One 2021 14;16(1):e0245281. Epub 2021 Jan 14.

UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Backgrounds: Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19.

Methods And Findings: We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit). The outcome was in-hospital mortality. Fine and Gray competing risks multivariate model (with discharge as a competing event) was used to develop a prediction rule for in-hospital mortality. Discrimination and calibration were assessed by the area under the receiver operating characteristic curve (AUC) and by Brier score in both the derivation and validation cohorts. Seven variables were independent risk factors for in-hospital mortality: age (Hazard Ratio [HR] 1.08, 95% Confidence Interval [CI] 1.07-1.09), male sex (HR 1.62, 95%CI 1.30-2.00), duration of symptoms before hospital admission <10 days (HR 1.72, 95%CI 1.39-2.12), diabetes (HR 1.21, 95%CI 1.02-1.45), coronary heart disease (HR 1.40 95% CI 1.09-1.80), chronic liver disease (HR 1.78, 95%CI 1.16-2.72), and lactate dehydrogenase levels at admission (HR 1.0003, 95%CI 1.0002-1.0005). The AUC was 0.822 (95%CI 0.722-0.922) in the derivation cohort and 0.820 (95%CI 0.724-0.920) in the validation cohort with good calibration. The prediction rule is freely available as a web-app (COVID-CALC: https://sites.google.com/community.unipa.it/covid-19riskpredictions/c19-rp).

Conclusions: A validated simple clinical prediction rule can promptly and accurately assess the risk for in-hospital mortality, improving triage and the management of patients with COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245281PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808616PMC
February 2021

Competing-risk analysis of coronavirus disease 2019 in-hospital mortality in a Northern Italian centre from SMAtteo COvid19 REgistry (SMACORE).

Sci Rep 2021 01 13;11(1):1137. Epub 2021 Jan 13.

U.O.C. Malattie Infettive I Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.

An accurate prediction of the clinical outcomes of European patients requiring hospitalisation for Coronavirus Disease 2019 (COVID-19) is lacking. The aim of the study is to identify predictors of in-hospital mortality and discharge in a cohort of Lombardy patients with COVID-19. All consecutive hospitalised patients from February 21st to March 30th, 2020, with confirmed COVID-19 from the IRCCS Policlinico San Matteo, Pavia, Lombardy, Italy, were included. In-hospital mortality and discharge were evaluated by competing risk analysis. The Fine and Gray model was fitted in order to estimate the effect of covariates on the cumulative incidence functions (CIFs) for in-hospital mortality and discharge. 426 adult patients [median age 68 (IQR 56 to 77 years)] were admitted with confirmed COVID-19 over a 5-week period; 292 (69%) were male. By 21 April 2020, 141 (33%) of these patients had died, 239 (56%) patients had been discharged and 46 (11%) were still hospitalised. Among these 46 patients, updated as of 30 May, 2020, 5 (10.9%) had died, 8 (17.4%) were still in ICU, 12 (26.1%) were transferred to lower intensity care units and 21 (45.7%) were discharged. Regression on the CIFs for in-hospital mortality showed that older age, male sex, number of comorbidities and hospital admission after March 4th were independent risk factors associated with in-hospital mortality. Older age, male sex and number of comorbidities definitively predicted in-hospital mortality in hospitalised patients with COVID-19.
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http://dx.doi.org/10.1038/s41598-020-80679-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806993PMC
January 2021

EBV DNA increase in COVID-19 patients with impaired lymphocyte subpopulation count.

Int J Infect Dis 2021 Mar 21;104:315-319. Epub 2020 Dec 21.

Molecular Virology Unit, Microbiology and VirologyDepartment, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy. Electronic address:

Objectives: The immunologic profile and opportunistic viral DNA increase were monitored in Italian patients with COVID-19 in order to identify markers of disease severity.

Methods: A total of 104 patients infected with SARS-CoV-2 were evaluated in the study. Of them, 42/104 (40.4%) were hospitalized in an intensive care unit (ICU) and 62/104(59.6%) in a sub-intensive care unit (SICU). Human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), Parvovirus B19 and Human Herpesvirus 6 virus reactivations were determined by real-time PCR, and lymphocyte subpopulation counts were determined by flow cytometry.

Results: Among opportunistic viruses, only EBV was consistently detected. EBV DNA was observed in 40/42 (95.2%) of the ICU patients and in 51/61 (83.6%) of the SICU patients. Comparing the two groups of patients, the EBV DNA median level among ICU patients was significantly higher than that observed in SICU patients. In parallel, a significant reduction of CD8 T cell and NK count in ICU patients as compared with SICU patients was observed (p<0.05). In contrast, B cell count was significantly increased in ICU patients (p=0.0172).

Conclusions: A correlation between reduced CD8 T cells and NK counts, EBV DNA levels and COVID-19 severity was observed. Other opportunistic viral infections were not observed. The relationship between EBV load and COVID-19 severity should be further evaluated in longitudinal studies.
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http://dx.doi.org/10.1016/j.ijid.2020.12.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833117PMC
March 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

Mortality reduction in 46 severe Covid-19 patients treated with hyperimmune plasma. A proof of concept single arm multicenter trial.

Haematologica 2020 12 1;105(12):2834-2840. Epub 2020 Dec 1.

Carlo Poma Hospital, ASST Mantova.

Hyperimmune plasma from Covid-19 convalescent is a potential treatment for severe Covid-19. We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease with moderate-to-severe Acute Respiratory Distress Syndrome, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma (neutralizing antibodies titer ≥1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety. The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged 63, 61% male, of them, 30 were on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Bilateral infiltrates on chest X-ray was present in 36 patients (84%). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days as compared to an expected 15% from the National Statistics and 30% from a small concurrent cohort of 23 patients. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related). In conclusion, Hyperimmune plasma in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma banking, development of standardized pharmaceutical products and monoclonal antibodies.
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http://dx.doi.org/10.3324/haematol.2020.261784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716363PMC
December 2020

COVID-19 and breast cancer: may the microbiome be the issue?

Future Oncol 2021 Jan 27;17(2):123-126. Epub 2020 Nov 27.

Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Viale Camillo Golgi 19, 27100, Pavia, Italy.

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http://dx.doi.org/10.2217/fon-2020-0764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720649PMC
January 2021

Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital.

Clin Nutr 2021 04 2;40(4):2469-2472. Epub 2020 Nov 2.

Clinical Nutrition and Dietetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Electronic address:

Background & Aims: Great interest has been raised by the possible protective role of vitamin D in coronavirus disease 2019 (COVID-19), but objective data on 25(OH)vitamin D deficiency in hospitalized COVID-19 patients are not conclusive. The aim of this study was to determine the prevalence of 25(OH)vitamin D deficiency in COVID-19 patients admitted to an Italian referral hospital and explore its association with clinical outcomes and the markers of disease severity.

Methods: In this single-center cohort study, 129 consecutive adult COVID-19 patients hospitalized in an Italian referral center were enrolled from March to April 2020. 25(OH)Vitamin D serum levels were assessed 48 h since hospital admission and categorized into: normal (≥30 ng/mL), insufficient (<30 - ≥20 ng/mL), moderately deficient (<20 - ≥10 ng/mL), severely deficient (<10 ng/mL).

Results: The prevalence of 25(OH)vitamin D insufficiency, moderate deficiency and severe deficiency was 13.2%, 22.5% and 54.3%, respectively. 25(OH)Vitamin D deficiency (<20 ng/mL) was not associated with COVID-19 clinical features and outcomes. Unexpectedly, after adjusting for major confounders, a significant positive association between increasing 25(OH)vitamin D levels and in-hospital mortality (on a continuous logarithmic scale, odds ratio = 1.73 [95% CI, 1.11 to 2.69]; P = .016) was observed.

Conclusions: Very low 25(OH)vitamin D levels were highly prevalent and suggestive of deficiency among our hospitalized severe COVID-19 patients, but low 25(OH)vitamin D levels were not associated with outcome variables. Whether 25(OH)vitamin D adequacy may influence clinical outcomes in COVID-19 and the unexpected correlation between higher 25(OH)vitamin D levels and mortality require further investigations by large intervention trials.
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http://dx.doi.org/10.1016/j.clnu.2020.10.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605851PMC
April 2021

Late-onset cutaneous eruption in hospitalized COVID-19 patients.

Eur J Dermatol 2020 Oct;30(5):621-622

Department of Clinical-Surgical, Diagnostic, and Pediatric Sciences, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1684/ejd.2020.3855DOI Listing
October 2020

Hemoperfusion with CytoSorb as Adjuvant Therapy in Critically Ill Patients with SARS-CoV2 Pneumonia.

Blood Purif 2020 Nov 12:1-6. Epub 2020 Nov 12.

Department of Anaesthesia and Intensive Care Unit, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy.

We report a preliminary experience of adjuvant therapy with Hemoperfusion (HP) in patients with Severe Acute Respiratory Syndrome-CoronaVirus 2 (SARS-CoV2) pneumonia. Currently, there are no approved treatments for CoronaVirus Disease 19 (COVID-19); however, therapeutic strategies based on the preclinical evidence include supportive measures, such as oxygen supplementation, antiviral, and anticoagulant agents. Despite these treatments, 10% of patients worsen and develop severe acute respiratory distress syndrome (ARDS). Since the pathogenic mechanism of ARDS is an uncontrolled inflammatory state, we speculate that removing inflammation effectors from blood may contrast tissue injury and improve clinical outcome. In a scenario of dramatic medical emergency, we conducted an observational study on 9 consecutive patients hospitalized in COVID Intensive Care Unit, where 5 of 9 consecutive patients were treated with HP, due to the emergency overload made it impossible to deliver blood purification in the other 4 patients. COVID-19 was diagnosed through the identification of virus sequences by reverse transcription-PCR on respiratory specimens. All patients had severe pneumonia requiring continuous positive airway pressure. HP was started in all patients 6-7 days after hospital admission. The treated patients (T) received 2 consecutive sessions of HP using CytoSorb cartridge. Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. Lymphocytopenia worsened in C but not in T. C-reactive protein decreased in both patients, but to a greater extent in T. IL-6, IL-8, and TNF-α decreased after HP, IL-10 did not change. Respiratory function remained stable and did not worsen in T compared to C. The limited sample size and observational study design preclude a sound statement about the potential effectiveness of HP in COVID-19 patients, but our experience suggests a potential therapeutic role of adjuvant CytoSorb HP in the early course of CO-VID-19 pneumonia. A randomized clinical trial is ongoing.
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http://dx.doi.org/10.1159/000511725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705939PMC
November 2020

Venous thromboembolism and COVID-19: a single center experience from an academic tertiary referral hospital of Northern Italy.

Intern Emerg Med 2020 Nov 8. Epub 2020 Nov 8.

Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p < 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p < 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p < 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in D-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE.
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http://dx.doi.org/10.1007/s11739-020-02550-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648897PMC
November 2020

Antiviral prophylaxis for hepatitis B carriers affected by diffuse large B cell lymphoma: a matter of survival.

Br J Haematol 2021 01 31;192(1):11-12. Epub 2020 Oct 31.

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

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http://dx.doi.org/10.1111/bjh.17143DOI Listing
January 2021

Unique immunological profile in patients with COVID-19.

Cell Mol Immunol 2021 03 15;18(3):604-612. Epub 2020 Oct 15.

Division of Infectious Diseases II and Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included. Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes, with an increased proportion of mature natural killer (NK) cells and low T-cell numbers. NK cells and CD8 T cells overexpressed T-cell immunoglobulin and mucin domain-3 (TIM-3) and CD69. NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1 (PD-1) positive cells and reduced frequencies of natural killer group 2 member D (NKG2D)-, DNAX accessory molecule-1 (DNAM-1)- and sialic acid-binding Ig-like lectin 7 (Siglec-7)-expressing NK cells, associated with a reduced ability to secrete interferon (IFN)γ. Patients with poor outcome showed a contraction of immature CD56 and an expansion of mature CD57 FcεRIγ adaptive NK cells compared to survivors. Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors. Of note, monocytes secreted abundant quantities of IL-6, IL-8, and IL-1β which persisted at lower levels several weeks after recovery with concomitant normalization of CD69, PD-1 and TIM-3 expression and restoration of CD8 T cell numbers. A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection, probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes. These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.
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http://dx.doi.org/10.1038/s41423-020-00557-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557230PMC
March 2021

Acute arterial and deep venous thromboembolism in COVID-19 patients: Risk factors and personalized therapy.

Surgery 2020 12 22;168(6):987-992. Epub 2020 Sep 22.

Vascular and Endovascular Surgery Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: The Lombardy region suffered severely during the acute phase of the coronavirus disease 2019 outbreak in Italy (Mar-Apr 2020) with 16,000 diagnosed coronavirus disease 2019-related deaths (49% of the total coronavirus disease 2019-related deaths in Italy). In the area surrounding Pavia during the critical stage of the outbreak (Mar-Apr 2020), 1,225 of the documented 4,200 deaths were related to coronavirus disease 2019 infection, with a mortality rate of 181/100,000 inhabitants and an increase in deaths of 138% compared with the same period during previous years. Our aim was to report the experience of the Department of Vascular Surgery of Pavia (Lombardy, Italy), including the lessons learned and future perspectives regarding the management of coronavirus disease 2019 patients who developed severe acute ischemia with impending lower limb loss or deep vein thrombosis.

Materials And Methods: We carried out a retrospective data collection of coronavirus disease 2019 patients with severe acute ischemia of the lower limbs or deep vein thrombosis, which we observed in our department during the period March 1, 2020, to April 30, 2020. Primary outcomes of the analysis were postoperative mortality for all patients and amputation rates only in those coronavirus disease 2019 patients suffering from acute lower limb ischemia. Secondary outcomes were the prevalence of the disease among admitted coronavirus disease 2019 patients, and any possible correlation among inflammatory parameters, thrombolytic status, and the presence of acute ischemia or deep vein thrombosis.

Results: We observed 38 patients (28 male) with severe coronavirus disease 2019 infection (6 with lower limb arterial thrombosis and 32 with deep vein thrombosis). The median patient age was 64 years (range 30-94 y). In the arterial group, 3 had thrombosis on plaque and 3 on healthy arteries ("simple" arterial thrombosis). All underwent operative or hybrid (open/endo) revascularization; 1 patient died from major organ failure and 1 patient underwent major amputation. In the deep vein thrombosis group, 9 (28%) patients died from major organ failure, despite aggressive medical therapy. In patients with simple arterial thrombosis and those with deep vein thrombosis, we observed a decrease in inflammatory parameters (C-reactive protein) and in D-dimer and fibrinogen after aggressive therapy (P <.001).

Conclusion: Our study confirms that critically ill, coronavirus disease 2019 patients who develop arterial and deep vein thrombosis have a high risk of mortality, but, if treated properly, there is an improvement in overall survival, especially in patients of 60 years of age or younger.
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http://dx.doi.org/10.1016/j.surg.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508538PMC
December 2020

Low risk of SARS-CoV-2 transmission by fomites in real-life conditions.

Lancet Infect Dis 2021 05 29;21(5):e112. Epub 2020 Sep 29.

Infectious Diseases I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

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http://dx.doi.org/10.1016/S1473-3099(20)30678-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524520PMC
May 2021