Publications by authors named "Paolo Grossi"

135 Publications

Successful Use of Heterologous CMV-Reactive T Lymphocyte to Treat Severe Refractory Cytomegalovirus (CMV) Infection in a Liver Transplanted Patient: Correlation of the Host Antiviral Immune Reconstitution with CMV Viral Load and CMV miRNome.

Microorganisms 2021 Mar 26;9(4). Epub 2021 Mar 26.

Department of Research, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Via E. Tricomi 5, 90127 Palermo, Italy.

Cytomegalovirus (CMV) infection is the most significant viral infection in hosts with compromised immune systems as solid organ transplant patients. Despite significant progress being made in the prevention of CMV disease in these patients, further therapeutic strategies for CMV disease and for the CMV reactivation prevention are needed. Here, we describe the outcome of the infusion of in vitro expanded CMV-reactive T-cells, taken from a healthy CMV-seropositive donor, in a liver-transplanted recipient with a refractory recurrent CMV. In this particular case, adoptive transfer of allogenic CMV-reactive T-lymphocytes resulted in the clearance of CMV infection and resolution of the pathological manifestations of the patient. In the study we also investigated circulating miRNAs, both cellular and viral, as potential biomarkers during the course of CMV infection. The results indicate that the infusion of allogenic CMV-reactive T-cells can be an effective strategy to treat CMV infection recurrence when the generation of autologous virus specific T cell clones is not possible.
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http://dx.doi.org/10.3390/microorganisms9040684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066103PMC
March 2021

The role of dalbavancin for Gram positive infections in the COVID-19 era: state of the art and future perspectives.

Expert Rev Anti Infect Ther 2021 Mar 16:1-10. Epub 2021 Mar 16.

Department of Medical and Surgical Sciences, University of Bologna - IRRCS Policlinico St Orsola, Bologna, Italy.

Introduction: The COVID-19 pandemic has dramatically challenged the national health systems worldwide in the last months. Dalbavancin is a novel antibiotic with a long plasmatic half-life and simplified weekly administration regimens, thus representing a promising option for the outpatient treatment of Gram-positive infections and the early discharge of hospitalized patients. Dalbavancin is approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). Many preliminary data seem to support its use in other indications, such as osteomyelitis, prosthetic joint infections, and infective endocarditis.

Areas Covered: A search in the literature using validated keywords (dalbavancin, Gram-positive infections, Gram-positive cocci, ABSSSI, intravenous treatment, and long-acting antibiotics) was conducted on biomedical bibliographic databases (PubMed and Embase) from 2004 to 30 September 2020. Results were analyzed during two consensus conferences with the aim to review the current evidence on dalbavancin in Gram-positive infections, mainly ABSSSI, osteomyelitis, and infective endocarditis, highlight the main limitations of available studies and suggest possible advantages of the molecule.

Expert Opinion: The board identifies some specific subgroups of patients with ABSSSIs who could mostly benefit from a treatment with dalbavancin and agrees that the design of homogenous and robust studies would allow a broader use of dalbavancin even in other clinical settings.
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http://dx.doi.org/10.1080/14787210.2021.1894130DOI Listing
March 2021

SARS-CoV-2 on Ocular Surfaces in a Cohort of Patients With COVID-19 From the Lombardy Region, Italy.

JAMA Ophthalmol 2021 Mar 4. Epub 2021 Mar 4.

Unit of Oral Medicine and Pathology, ASST dei Sette Laghi, Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Importance: Since February 2020, coronavirus disease 2019 (COVID-19) has spread rapidly all over the world, with an epidemiological cluster in Lombardy, Italy. The viral communicability may be mediated by various body fluids, but insufficient information is available on the presence of the virus in human tears.

Objectives: To investigate the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in tears collected from patients with COVID-19 by means of real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) assay and to assess the association of virus presence with concomitant clinical conditions.

Design, Setting, And Participants: Cross-sectional study conducted between April 9 and May 5, 2020. The setting was intensive care units at Azienda Socio-Sanitaria Territoriale (ASST) Sette-Laghi Hospital, University of Insubria, in Varese, Lombardy, Italy. A conjunctival swab was performed in 91 patients hospitalized for COVID-19, which was clinically diagnosed by rRT-PCR assay on nasopharyngeal swabs and by radiological imaging. Conjunctival swabs from 17 additional healthy volunteer participants with no symptoms of COVID-19 were examined to evaluate the availability and applicability of the conjunctival swab test.

Exposure: SARS-CoV-2 detection by means of rRT-PCR assay performed on the collected samples obtained by conjunctival swabs.

Main Outcomes And Measures: Conjunctival swab and nasopharyngeal swab results are reported, as well as demographic and clinical data.

Results: A total of 108 participants (mean [SD] age, 58.7 [14.2] years; 55 female and 53 male) were tested for SARS-CoV-2 using rRT-PCR assay, including 91 patients hospitalized with COVID-19 and 17 were healthy volunteers. SARS-CoV-2 was found on the ocular surface in 52 of 91 patients with COVID-19 (57.1%; 95% CI, 46.3%-67.5%), with a wide variability in the mean viral load from both eyes. Among a subset of 41 patients, concordance of 63.0% (95% CI, 41.0%-81.0%) was found between positive conjunctival and nasopharyngeal swab test results when performed within 2 days of each other. In 17 of these patients, nasopharyngeal swab results were negative for SARS-CoV-2. In 10 of these 17 patients, conjunctival swab results were positive for the virus.

Conclusions And Relevance: In this study, SARS-CoV-2 RNA was found on the ocular surface in a large part of this cohort of patients with COVID-19, although the infectivity of this material could not be determined. Because patients may have positive test results with a conjunctival swab and negative results with a nasopharyngeal swab, use of the slightly invasive conjunctival swab may be considered as a supplementary diagnostic test.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.5464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934077PMC
March 2021

Liver transplantation performed in a SARS-CoV-2 positive hospitalized recipient using a SARS-CoV-2 infected donor.

Am J Transplant 2021 Feb 23. Epub 2021 Feb 23.

Hepato-Pancreato-Biliary and Transplant Unit, University of Rome Tor Vergata, Rome, Italy.

The coronavirus disease 2019 (COVID-19) is a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 currently affected more than 108 million people worldwide with a fatality rate of 2.2%. Herein, we report the first case of liver transplantation (LT) performed with a liver procured from a SARS-CoV-2 positive donor. The recipient was a 35-year-old SARS-CoV-2 positive female patient affected by severe end-stage HBV-HDV-related liver disease (model of end-stage liver disease = 32) who had neutralizing SARS-CoV-2 antibodies (titers 1:320) at time of LT. The LT was successful, and the graft is functioning two months after surgery. The recipient cleared the SARS-CoV-2 infection 1 month after LT. The current case shows that the prompt use of SARS-CoV-2 infected liver donors offers an invaluable life-saving opportunity for SARS-CoV-2 positive wait-listed patients who developed neutralizing SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1111/ajt.16548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013325PMC
February 2021

Ceftazidime-avibactam use for KPC-Kp infections: a retrospective observational multicenter study.

Clin Infect Dis 2021 Feb 22. Epub 2021 Feb 22.

Clinical Infectious Diseases, Tor Vergata University, Roma Italy.

Background: A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae (CRE).

Methods: We retrospectively analyzed observational data on the use and outcomes of CAZ-AVI therapy for infections caused by KPC-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens vs. CAZ-AVI monotherapy.

Results: The cohort comprised 577 adults with bloodstream infections (BSIs) (n=391) or non-bacteremic infections (nBSIs) involving mainly the urinary tract, lower respiratory tract, intra-abdominal structures. All received treatment with CAZ-AVI alone (n=165) or with one or more other active antimicrobials (n=412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no statistically significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs. 25.0%, P=0.79). In multivariate analysis, mortality was positively associated with the presence at infection onset of septic shock (P=0.002), neutropenia (P <0.001), or an INCREMENT score >8 (P=0.01); with LRTI (P=0.04); and with CAZ-AVI dose adjustment for renal function (P=0.01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P=0.006). All associations remained significant after propensity score adjustment.

Conclusions: CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug's seemingly more limited efficacy in LRTIs and the potential survival benefits of prolonging CAZ-AVI infusions to 3 hours or more.
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http://dx.doi.org/10.1093/cid/ciab176DOI Listing
February 2021

Imported SARS-CoV-2 Variant P.1 in Traveler Returning from Brazil to Italy.

Emerg Infect Dis 2021 04 10;27(4):1249-1251. Epub 2021 Feb 10.

We report an imported case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant P.1 detected in an asymptomatic traveler who arrived in Italy on an indirect flight from Brazil. This case shows the risk for introduction of SARS-CoV-2 variants from indirect flights and the need for continued SARS-CoV-2 surveillance.
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http://dx.doi.org/10.3201/eid2704.210183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007292PMC
April 2021

Development of a Risk Prediction Model for Carbapenem-Resistant Enterobacteriaceae Infection after Liver Transplantation: A Multinational Cohort Study.

Clin Infect Dis 2021 Feb 10. Epub 2021 Feb 10.

Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

Background: Patients colonized with carbapenem resistant Enterobacteriaceae (CRE) are at higher risk of developing CRE infection after liver transplantation (LT) with associated high morbidity and mortality. Prediction model for CRE infection after LT among carriers could be useful to target preventive strategies.

Methods: Multinational multicenter cohort study of consecutive adult patients underwent LT and colonized with CRE before or after LT, from January 2010 to December 2017. Risk factors for CRE infection were analyzed by univariate analysis and by Fine-Gray sub-distribution hazard model, with death as competing event. A nomogram to predict 30- and 60-day CRE infection risk was created.

Results: 840 LT recipients found to be colonized with CRE before (n=203) or after (n=637) LT were enrolled. CRE infection was diagnosed in 250 (29.7%) patients within 19 (IQR 9-42) days after LT. Pre-and post-LT colonization, multisite post-LT colonization, prolonged mechanical ventilation, acute renal injury, and surgical re-intervention were retained in the prediction model. Median 30 and 60-day predicted risk was 15% (IQR 11-24%) and 21% (IQR 15-33%), respectively. Discrimination and prediction accuracy for CRE infection was acceptable on derivation (AUC 74.6, Brier index 16.3) and bootstrapped validation dataset (AUC 73.9, Brier index 16.6). Decision-curve analysis suggested net benefit of model-directed intervention over default strategies (treat all, treat none) when CRE infection probability exceeded 10%. The risk prediction model is freely available as mobile application at https://idbologna.shinyapps.io/CREPostOLTPredictionModel/.

Conclusions: Our clinical prediction tool could enable better targeting interventions for CRE infection after transplant.
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http://dx.doi.org/10.1093/cid/ciab109DOI Listing
February 2021

EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.

J Hepatol 2021 04 6;74(4):944-951. Epub 2021 Feb 6.

Liver Unit, Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem, Israel.

According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.
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http://dx.doi.org/10.1016/j.jhep.2021.01.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867401PMC
April 2021

Therapeutic strategies for severe COVID-19: a position paper from the Italian Society of Infectious and Tropical Diseases (SIMIT).

Clin Microbiol Infect 2021 Mar 18;27(3):389-395. Epub 2021 Jan 18.

Unit of Emerging and Immunosuppressed Infectious Diseases, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, Ancona, Italy.

Scope: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic, reaching almost one million death worldwide. At present standard treatment for coronavirus disease 2019 (COVID-19) is not well defined because the evidence, either from randomized or observational studies, with conflicting results, has led to rapid changes in treatment guidelines. Our aim was to narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and interpretation of the data by experts who are treating patients in the frontline setting.

Methods: The panel conducted a detailed review of the literature and eventual press releases from randomized clinical trials for each possible available treatment. Inductive PubMed search waws performed for publications relevant to the topic, including all clinical trials conducted. The result was a flowchart with treatment indications for patients with COVID-19.

Implications: After 6 months of a pandemic situation and before a possible second coronavirus wave descends on Europe, it is important to evaluate which drugs proved to be effective while also considering that results from many randomized clinical trials are still awaited. Indeed, among treatments for COVID-19, only glucocorticoids have resulted in an association with a significant decrease in mortality in published randomized controlled trials. New therapeutic strategies are urgently needed.
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http://dx.doi.org/10.1016/j.cmi.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833273PMC
March 2021

Pilot Study: Long-Term Shedding of SARS-CoV-2 in Urine: A Threat for Dispersal in Wastewater.

Front Public Health 2020;8:569209. Epub 2020 Nov 23.

Pathology Unit, Azienda Socio Sanitaria Territoriale (ASST) Sette Laghi, Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Only 4 months after the beginning of SARS-CoV-2 epidemic, the world is facing a global pandemic due to a complex and insidious virus that today constantly poses new challenges. In this study, we highlight a persistent shedding of SARS-CoV-2 RNA into the urine, even in patients with a negative nasopharyngeal swab and in patients considered recovered. What does it mean? Besides the fact that the kidney is a probable site of viral replication, the prolonged viral excretion is a matter of great concern for our drainage system contamination.
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http://dx.doi.org/10.3389/fpubh.2020.569209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719751PMC
January 2021

Incidence and outcome of SARS-CoV-2 infection on solid organ transplantation recipients: A nationwide population-based study.

Am J Transplant 2020 Dec 5. Epub 2020 Dec 5.

Italian National Transplant Center, Istituto Superiore di Sanità, Rome, Italy.

Since February 21 2020, when the Italian National Institute of Health (Istituto Superiore di Sanità-ISS) reported the first autochthonous case of infection, a dedicated surveillance system for SARS-CoV-2-positive (COVID+) cases has been created in Italy. These data were cross-referenced with those inside the Information Transplant System in order to assess the cumulative incidence (CI) and the outcome of SARS-COV-2 infection in solid organ transplant recipients (SOTRs) who are assumed to be most at risk. We compared our results with those of COVID+ nontransplanted patients (Non-SOTRs) with follow-up through September 30, 2020. The CI of SARS-CoV-2 infection in SOTRs was 1.02%, higher than in COVID+ Non-SOTRs (0.4%, p < .05) with a greater risk in the Lombardy region (2.89%). The CI by type of organ transplant was higher for heart (CI 1.57%, incidence rate ratio [IRR] 1.36) and lower for liver (CI 0.63%, IRR 0.54). The 60-day CI of mortality was 30.6%, twice as much that of COVID+ Non-SOTRs (15.4%) with a 60-day gender and age adjusted odds ratio (adjusted-OR) of 3.83 for COVID+ SOTRs (95% confidence interval [3.03-4.85]). The lowest 60-day adjusted-OR was observed in liver SOTRs (OR 0.46, 95% confidence interval [0.25-0.86]). More detailed studies on disease management and evolution will be necessary in these patients at greater risk of COVID-19.
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http://dx.doi.org/10.1111/ajt.16428DOI Listing
December 2020

Efficacy of β-lactam/β-lactamase inhibitors to treat extended-spectrum beta-lactamase-producing Enterobacterales bacteremia secondary to urinary tract infection in kidney transplant recipients (INCREMENT-SOT Project).

Transpl Infect Dis 2020 Nov 22:e13520. Epub 2020 Nov 22.

Clinical Microbiology ID & Infection control, Global Hospitals, Hyderabad, India.

Background: Whether active therapy with β-lactam/β-lactamase inhibitors (BLBLI) is as affective as carbapenems for extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) bloodstream infection (BSI) secondary to urinary tract infection (UTI) in kidney transplant recipients (KTRs) remains unclear.

Methods: We retrospectively evaluated 306 KTR admitted to 30 centers from January 2014 to October 2016. Therapeutic failure (lack of cure or clinical improvement and/or death from any cause) at days 7 and 30 from ESBL-E BSI onset was the primary and secondary study outcomes, respectively.

Results: Therapeutic failure at days 7 and 30 occurred in 8.2% (25/306) and 13.4% (41/306) of patients. Hospital-acquired BSI (adjusted OR [aOR]: 4.10; 95% confidence interval [CI]: 1.50-11.20) and Pitt score (aOR: 1.47; 95% CI: 1.21-1.77) were independently associated with therapeutic failure at day 7. Age-adjusted Charlson Index (aOR: 1.25; 95% CI: 1.05-1.48), Pitt score (aOR: 1.72; 95% CI: 1.35-2.17), and lymphocyte count ≤500 cells/μL at presentation (aOR: 3.16; 95% CI: 1.42-7.06) predicted therapeutic failure at day 30. Carbapenem monotherapy (68.6%, primarily meropenem) was the most frequent active therapy, followed by BLBLI monotherapy (10.8%, mostly piperacillin-tazobactam). Propensity score (PS)-adjusted models revealed no significant impact of the choice of active therapy (carbapenem-containing vs any other regimen, BLBLI- vs carbapenem-based monotherapy) within the first 72 hours on any of the study outcomes.

Conclusions: Our data suggest that active therapy based on BLBLI may be as effective as carbapenem-containing regimens for ESBL-E BSI secondary to UTI in the specific population of KTR. Potential residual confounding and unpowered sample size cannot be excluded (ClinicalTrials.gov identifier: NCT02852902).
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http://dx.doi.org/10.1111/tid.13520DOI Listing
November 2020

HLA and AB0 Polymorphisms May Influence SARS-CoV-2 Infection and COVID-19 Severity.

Transplantation 2021 01;105(1):193-200

National Transplant Center, Istituto Superiore di Sanità, Roma, Italy.

Background: SARS-CoV-2 infection is heterogeneous in clinical presentation and disease evolution. To investigate whether immune response to the virus can be influenced by genetic factors, we compared HLA and AB0 frequencies in organ transplant recipients and waitlisted patients according to presence or absence of SARS-CoV-2 infection.

Methods: A retrospective analysis was performed on an Italian cohort composed by transplanted and waitlisted patients in a January 2002 to March 2020 time frame. Data from this cohort were merged with the Italian registry of COVID+ subjects, evaluating infection status of transplanted and waitlisted patients. A total of 56 304 cases were studied with the aim of comparing HLA and AB0 frequencies according to the presence (n = 265, COVID+) or absence (n = 56 039, COVID-) of SARS-CoV-2 infection.

Results: The cumulative incidence rate of COVID-19 was 0.112% in the Italian population and 0.462% in waitlisted/transplanted patients (OR = 4.2; 95% CI, 3.7-4.7; P < 0.0001). HLA-DRB1*08 was more frequent in COVID+ (9.7% and 5.2%: OR = 1.9, 95% CI, 1.2-3.1; P = 0.003; Pc = 0.036). In COVID+ patients, HLA-DRB1*08 was correlated to mortality (6.9% in living versus 17.5% in deceased: OR = 2.9, 95% CI, 1.15-7.21; P = 0.023). Peptide binding prediction analyses showed that these DRB1*08 alleles were unable to bind any of the viral peptides with high affinity. Finally, blood group A was more frequent in COVID+ (45.5%) than COVID- patients (39.0%; OR = 1.3; 95% CI, 1.02-1.66; P = 0.03).

Conclusions: Although preliminary, these results suggest that HLA antigens may influence SARS-CoV-2 infection and clinical evolution of COVID-19 and confirm that blood group A individuals are at greater risk of infection, providing clues on the spread of the disease and indications about infection prognosis and vaccination strategies.
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http://dx.doi.org/10.1097/TP.0000000000003507DOI Listing
January 2021

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study.

Lancet Haematol 2020 Oct 13;7(10):e737-e745. Epub 2020 Aug 13.

Hematology, University Hospital Sant'Andrea, Sapienza, Rome, Italy; Department of Clinical and Molecular Medicine, Sapienza, University of Rome, Rome, Italy.

Background: Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19.

Methods: This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing.

Findings: We enrolled 536 patients with a median follow-up of 20 days (IQR 10-34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2·04 (95% CI 1·77-2·34) in our whole study cohort and 3·72 (2·86-4·64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41·3 (38·1-44·9). Older age (hazard ratio 1·03, 95% CI 1·01-1·05); progressive disease status (2·10, 1·41-3·12); diagnosis of acute myeloid leukaemia (3·49, 1·56-7·81), indolent non-Hodgin lymphoma (2·19, 1·07-4·48), aggressive non-Hodgkin lymphoma (2·56, 1·34-4·89), or plasma cell neoplasms (2·48, 1·31-4·69), and severe or critical COVID-19 (4·08, 2·73-6·09) were associated with worse overall survival.

Interpretation: This study adds to the evidence that patients with haematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19. The high mortality among patients with haematological malignancies hospitalised with COVID-19 highlights the need for aggressive infection prevention strategies, at least until effective vaccination or treatment strategies are available.

Funding: Associazione italiana contro le leucemie, linfomi e mieloma-Varese Onlus.
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http://dx.doi.org/10.1016/S2352-3026(20)30251-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426107PMC
October 2020

Association of immigration background with kidney graft function in a publicly funded health system: a nationwide retrospective cohort study in Italy.

Transpl Int 2020 11 22;33(11):1405-1416. Epub 2020 Jul 22.

Italian National Transplant Center (CNT), Istituto Superiore di Sanità, Rome, Italy.

The impact of immigration background on kidney graft function (eGFR) is unknown. Italy has a publicly funded health system with universal coverage. Since immigration from non-European Union (EU) countries beyond Eastern Europe is a recent and extensive phenomenon, Italy is a rather unique setting for studying the effect of immigration status as a socioeconomic and cultural condition. We retrospectively identified all adult deceased donor kidney transplant recipients (KTRs) in Italy (2010-2015) and followed them until death, dialysis or 5-years post-transplantation; 6346 were EU-born, 161 Eastern European-born, and 490 non-European-born. We examined changes in eGFR after 1-year post-transplant using multivariable-adjusted joint longitudinal survival random-intercept Cox regression. Compared to EU-born KTRs, in non-European-born KTRs the adjusted average yearly eGFR decline was -0.96 ml/min/year (95% confidence interval: -1.48 to -0.45; P < 0.001), whereas it was similar in Eastern European-born KTRs [+0.02 ml/min/year (-0.77 to +0.81; P = 0.96)]. Adjusted 5-year transplant survival did not statistically differ between non-European-born, Eastern European-born, and EU-born. In those surviving beyond 1-year, it was 91.8% in EU-born (87.1-96.8), 92.5% in Eastern European-born (86.1-99.4), and 89.3% in non-European-born KTRs (83.0-96.0). This study provides evidence that among EU KTRs, non-European immigration background is associated with eGFR decline.
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http://dx.doi.org/10.1111/tri.13688DOI Listing
November 2020

Recurrence of immune thrombocytopenia at the time of SARS-CoV-2 infection.

Ann Hematol 2020 08 11;99(8):1951-1952. Epub 2020 Jun 11.

Infectious and Tropical Diseases, University Hospital "Ospedale di Circolo e Fondazione Macchi" - ASST Sette Laghi, University of Insubria, Varese, Italy.

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http://dx.doi.org/10.1007/s00277-020-04130-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288620PMC
August 2020

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study).

Open Forum Infect Dis 2020 May 21;7(5):ofaa139. Epub 2020 Apr 21.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Few data are reported in the literature about the outcome of patients with severe extended-spectrum β-lactamase-producing (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.

Methods: A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.

Results: C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index >4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; < .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; < .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; < .001) were associated with clinical success.

Conclusions: Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing . Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT.
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http://dx.doi.org/10.1093/ofid/ofaa139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237821PMC
May 2020

Utilization of hepatitis C virus-infected organ donors in cardiothoracic transplantation: An ISHLT expert consensus statement.

J Heart Lung Transplant 2020 05 19;39(5):418-432. Epub 2020 Mar 19.

The advent of therapies for successful treatment of hepatitis C virus has allowed the heart and lung transplant community to re-explore the use of hepatitis C virus-positive donors for organ transplantation, with a benefit for many terminally ill patients. The consensus statements provided herein represent the current state of knowledge and expertise in this area, which we expect will continue to rapidly evolve over the next few years.
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http://dx.doi.org/10.1016/j.healun.2020.03.004DOI Listing
May 2020

How can we optimise antifungal use in a solid organ transplant centre? Local epidemiology and antifungal stewardship implementation: A single-centre study.

Mycoses 2020 Jul 18;63(7):746-754. Epub 2020 May 18.

Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy.

Purpose: We aimed to implement and to assess the impact of the antifungal stewardship programme (AFSp) on prescription appropriateness of antifungals, management and outcomes of candidaemia patients, and antifungal consumption and costs at our solid organ transplant (SOT) institute.

Methods: Local epidemiology of invasive fungal infections (IFIs) from 2009 to 2017 was analysed in order to prepare an effective AFSp, implemented in January 2018. It included suspension of empirical antifungal prescriptions after 72 hours (antifungal time-out), automated alert and infectious disease (ID) consult for empirical prescriptions and for every patient with IFI, and indication for step-down to oral fluconazole when possible. We used process measures and results measures to assess the effects of the implemented programme.

Results: The ASFp led to significant improvements in selection of the appropriate antifungal (40.5% in pre-AFS vs 78.6% in post-AFS), correct dosing (51.2% vs 79.8%), correct length of treatment (55.9% vs 75%) and better management of patients with candidaemia. Analysis of prescribed empirical antifungal revealed that defined daily doses (DDDs) per 100 patient days decreased by 36.7% in 2018 compared to the average of pre-AFSp period, with important savings in costs.

Conclusion: This AFSp led to a better use of antifungal drugs in terms of appropriateness and consumption, with stable clinical and microbiological outcomes in patients with IFI.
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http://dx.doi.org/10.1111/myc.13098DOI Listing
July 2020

Direct-acting antivirals in relapsed or refractory hepatitis C virus-associated diffuse large B-cell lymphoma.

Leuk Lymphoma 2020 09 28;61(9):2122-2128. Epub 2020 Apr 28.

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Recent studies have demonstrated feasibility and substantial benefit of direct-acting antivirals (DAAs) administration during or after first-line immune-chemotherapy (I-CT) in patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphomas (DLBCL). However, data on DAAs used during or after salvage treatments are still lacking. In this study we assessed clinical and virological outcome in 11 patients with relapsed ( = 7) or refractory ( = 4) HCV-positive DLBCL. DAAs were given either concurrently ( = 3) or subsequent ( = 8) to salvage I-CT. Most patients (10 of 11) received sofosbuvir-based regimens. All patients completed their planned courses of DAAs and achieved sustained virological response. DAAs were well tolerated, with no grade ≥2 adverse events. At a median follow-up of 3.6 years four patients died (4-year OS: 76%). In conclusion, we provide evidence that DAAs in HCV-positive relapsed/refractory DLBCL are extremely safe and effective, suggesting that they should be used if HCV eradication was not instituted before.
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http://dx.doi.org/10.1080/10428194.2020.1755859DOI Listing
September 2020

Saliva is a reliable tool to detect SARS-CoV-2.

J Infect 2020 07 14;81(1):e45-e50. Epub 2020 Apr 14.

Laboratory of Clinical Microbiology, ASST dei Sette Laghi, Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Objectives: This study analyzed salivary samples of COVID-19 patients and compared the results with their clinical and laboratory data.

Methods: Salivary samples of 25 COVID-19 patients were analyzed by rRT-PCR. The following data were collected: age, sex, comorbidities, drugs. Lactate dehydrogenase (LDH) and ultrasensitive reactive C protein (usRCP) values were registered on the same day when a salivary swab was collected. Prevalence of positivity in saliva and association between clinical data and the cycle threshold as a semiquantitative indicator of viral load were considered.

Results: Twenty-five subjects were recruited into this study, 17 males and 8 females. The mean age was 61.5 +/- 11.2 years. Cardiovascular and/or dysmetabolic disorders were observed in 65.22% of cases. All the samples tested positive for the presence of SARS-CoV-2, while there was an inverse association between LDH and Ct values. Two patients showed positive salivary results on the same days when their pharyngeal or respiratory swabs showed conversion.

Conclusions: Saliva is a reliable tool to detect SARS-CoV-2. The role of saliva in COVID-19 diagnosis could not be limited to a qualitative detection of the virus, but it may also provide information about the clinical evolution of the disease.
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http://dx.doi.org/10.1016/j.jinf.2020.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194805PMC
July 2020

Novel Coronavirus-19 (COVID-19) in the immunocompromised transplant recipient: #Flatteningthecurve.

Am J Transplant 2020 Jul 12;20(7):1765-1767. Epub 2020 Apr 12.

Infectious Diseases Department, University of Insubria, Varese, Italy.

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http://dx.doi.org/10.1111/ajt.15890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228206PMC
July 2020

COVID-19: A global transplant perspective on successfully navigating a pandemic.

Am J Transplant 2020 Jul 12;20(7):1773-1779. Epub 2020 Apr 12.

Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.

The COVID-19 pandemic has rapidly evolved and changed our way of life in an unprecedented manner. The emergence of COVID-19 has impacted transplantation worldwide. The impact has not been just restricted to issues pertaining to donors or recipients, but also health-care resource utilization as the intensity of cases in certain jurisdictions exceeds available capacity. Here we provide a personal viewpoint representing different jurisdictions from around the world in order to outline the impact of the current COVID-19 pandemic on organ transplantation. Based on our collective experience, we discuss mitigation strategies such as donor screening, resource planning, and a staged approach to transplant volume considerations as local resource issues demand. We also discuss issues related to transplant-related research during the pandemic, the role of transplant infectious diseases, and the influence of transplant societies for education and disseminating current information.
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http://dx.doi.org/10.1111/ajt.15876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228301PMC
July 2020

Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort.

Liver Int 2020 04 3;40(4):769-777. Epub 2020 Feb 3.

ASST Bergamo Ovest, Treviglio, Italy.

Background & Aims: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap.

Methods: Sustained virological response 12 weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression.

Results: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF + DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF + DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P = .065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P = .007) and lower median pretreatment Log HCV-RNA (5.87 vs 6.20, P = .001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF + DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12.

Conclusions: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF + DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this genotype.
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http://dx.doi.org/10.1111/liv.14386DOI Listing
April 2020

CMV infection management in transplant patients in Italy.

J Clin Virol 2020 02 9;123:104211. Epub 2019 Nov 9.

Infectious Disease Unit, Policlinic Foundation Tor Vergata, Rome, Italy; Department of Oncology and Oncohematology, University of Milan, Italy; Department of Clinical Virology, ASST Niguarda, Milan, Italy. Electronic address:

Transplant represents an effective strategy in the management of chronic organ dysfunction. Nonetheless, life threatening risks remain, especially in the post-transplant; among them, human cytomegalovirus (CMV) is a major concern, currently causing active infections in at least one-third of transplant recipients. Microbiologist and transplant scientific societies redefined guidance on CMV disease prevention and the best use for universal prophylaxis and pre-emptive virological monitoring. Developments in molecular diagnostic supported the spread of the pre-emptive strategy, and quantitative Real Time-PCR assays has unravelled the potential of viral load measurement as a predictor of the infection development in CMV post-transplant management. However, despite the WHO 1st CMV International Standard, the standardization of diagnostic and clinical practice has been limited by the absence of algorithms for calculating conversion factor to International Units and the lack of shared monitoring procedure, both at national and international level. At a regional level, the Italian scientific societies, AMCLI (Italian Clinical Microbiologist Association), SITO (Organ Transplant Italian Society), GITMO (Italian Group for Bone Marrow Transplant), recently tried to define a consensus for post-transplant monitoring. The concerted practice encompasses molecular quantitative PCR assays technical aspects and endorses the relevance of immunologic monitoring for improvement in patient risk stratification and prognosis. Here, we provide an overview of the state of the art of CMV management strategies, with a specific focus on the clinical practices and on the scientific societies' initiatives that aim to implement international standardization guidelines at a national level.
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http://dx.doi.org/10.1016/j.jcv.2019.104211DOI Listing
February 2020

Renal safety in 3264 HCV patients treated with DAA-based regimens: Results from a large Italian real-life study.

Dig Liver Dis 2020 02 6;52(2):190-198. Epub 2019 Dec 6.

ASST Melegnano Martesana, Internal Medicine, Milan, Italy.

Background: Sofosbuvir (SOF)-based regimens have been associated with renal function worsening in HCV patients with estimated glomerular filtration rate (eGFR) ≤ 45 ml/min, but further investigations are lacking.

Aim: To assess renal safety in a large cohort of DAA-treated HCV patients with any chronic kidney disease (CKD).

Methods: All HCV patients treated with DAA in Lombardy (December 2014-November 2017) with available kidney function tests during and off-treatment were included.

Results: Among 3264 patients [65% males, 67% cirrhotics, eGFR 88 (9-264) ml/min], CKD stage was 3 in 9.5% and 4/5 in 0.7%. 79% and 73% patients received SOF and RBV, respectively. During DAA, eGFR declined in CKD-1 (p < 0.0001) and CKD-2 (p = 0.0002) patients, with corresponding rates of CKD stage reduction of 25% and 8%. Conversely, eGFR improved in lower CKD stages (p < 0.0001 in CKD-3a, p = 0.0007 in CKD-3b, p = 0.024 in CKD-4/5), with 33-45% rates of CKD improvement. Changes in eGFR and CKD distribution persisted at SVR. Baseline independent predictors of CKD worsening at EOT and SVR were age (p < 0.0001), higher baseline CKD stages (p < 0.0001) and AH (p = 0.010 and p < 0.0001, respectively).

Conclusions: During DAA, eGFR significantly declined in patients with preserved renal function and improved in those with lower CKD stages, without reverting upon drug discontinuation.
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http://dx.doi.org/10.1016/j.dld.2019.11.006DOI Listing
February 2020

Heart or lung transplant outcomes in HIV-infected recipients.

J Heart Lung Transplant 2019 12 25;38(12):1296-1305. Epub 2019 Sep 25.

Division of Infectious Diseases, Mt. Sinai Hospital, New York, New York.

Background: Limited published data exist on outcomes related to heart and/or lung transplantation in human immunodeficiency virus (HIV)-infected individuals.

Methods: We conducted a multicenter retrospective study of heart and lung transplantation in HIV-infected patients and describe key transplant- and HIV-related outcomes.

Results: We identified 29 HIV-infected thoracic transplant recipients (21 heart, 7 lung, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared with an International Society for Heart and Lung Transplantation registry cohort, we demonstrated similar 1-, 3-, and 5-year patient and allograft survivals for each organ type with a median follow up of 1,064 (range, 184-3,745) days for heart and 1,540 (range, 116-3,206) days for lung recipients. At 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Risk factors for rejection were inconclusive, likely because of small numbers, but may be related to cautious early immunosuppression and infrequent use of induction therapy. Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs). Median CD4 counts changed from baseline to 1 year from 399 to 411 cells/µl for HTRs and 638 to 280 cells/µl for LTRs. Acquired immunodeficiency syndrome-related events, including infections and malignancies, were rare. Rates of severe renal dysfunction suggest a need to modify nephrotoxic anti-retrovirals and/or immunosuppressants.

Conclusions: HIV-infected HTRs and LTRs have similar survival rates to their HIV-uninfected counterparts. Although optimal immunosuppression is not defined, it should be at least as aggressive as that for HIV-uninfected recipients. Such data may help pave the way for the use of hearts and lungs from HIV-infected donors in HIV-infected recipients through HIV Organ Policy Equity Act protocols.
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http://dx.doi.org/10.1016/j.healun.2019.09.011DOI Listing
December 2019