Publications by authors named "Cristina Mussini"

269 Publications

Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection.

PLoS One 2021 23;16(2):e0247275. Epub 2021 Feb 23.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria, Policlinico of Modena, Modena, Italy.

Background: The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients' profile.

Methods: Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day 6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort.

Results: 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively.

Conclusions: Our score could assist clinicians in identifying, early after tocilizumab administration, patients who are likely to progress to mechanical ventilation or death, so that they could be selected for eventual rescue therapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247275PLOS
February 2021

Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia.

AIDS Res Hum Retroviruses 2021 Feb 23. Epub 2021 Feb 23.

University of Modena and Reggio Emilia. Institute of Infectious Diseases and Metabolic Clinic, via del pozzo 71, Modena, Italy, 41125;

Background The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with COVID-19 pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment duration. Secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDI) and died during hospitalization. Methods This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Results 273 patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p>0.05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days, p=0.9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p<0.0001), more pronounced in patients undergoing DRV/c for less than 5 days. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p=0.03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. Conclusion DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.
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http://dx.doi.org/10.1089/AID.2020.0305DOI Listing
February 2021

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

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

Department of Medical and Surgical Sciences - University of Bologna, Bologna, 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

Lamivudine plus dolutegravir improves bone mineral density compared to emtricitabine/tenofovir alafenamide plus an integrase inhibitor.

AIDS Res Hum Retroviruses 2021 Feb 15. Epub 2021 Feb 15.

Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, 60234, L.go F. Vito 1, Roma, Italy, 00168;

N/A.
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http://dx.doi.org/10.1089/AID.2020.0274DOI Listing
February 2021

Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen).

BMJ Open 2021 Feb 8;11(2):e040210. Epub 2021 Feb 8.

Division of Infectious Diseases, Rambam Health Care Campus, Haifa, Israel

Introduction: The optimal treatment for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae bloodstream infections has yet to be defined. Retrospective studies have shown conflicting results, with most data suggesting the non-inferiority of beta-lactam-beta-lactamase inhibitor combinations compared with carbapenems. However, the recently published MERINO trial failed to demonstrate the non-inferiority of piperacillin-tazobactam to meropenem. The potential implications of the MERINO trial are profound, as widespread adoption of carbapenem treatment will have detrimental effects on antimicrobial stewardship in areas endemic for ESBL and carbapenem-resistant bacteria. Therefore, we believe that it is justified to re-examine the comparison in a second randomised controlled trial prior to changing clinical practice.

Methods And Analysis: PeterPen is a multicentre, investigator-initiated, open-label, randomised controlled non-inferiority trial, comparing piperacillin-tazobactam with meropenem for third-generation cephalosporin-resistant and bloodstream infections. The study is currently being conducted in six centres in Israel and one in Canada with other centres from Israel, Italy and Canada expected to join. The two primary outcomes are all-cause mortality at day 30 from enrolment and treatment failure at day seven (death, fever above 38°C in the last 48 hours, continuous symptoms, increasing Sequential Organ Failure Assessment Score or persistent blood cultures with the index pathogen). A sample size of 1084 patients was calculated for the mortality endpoint assuming a 12.5% mortality rate in the control group with a 5% non-inferiority margin and assuming 100% follow-up for this outcome.

Ethics And Dissemination: The study is approved by local and national ethics committees as required. Results will be published, and trial data will be made available.

Trial Registration Numbers: ClinicalTrials.gov Registry (NCT03671967); Israeli Ministry of Health Trials Registry (MOH_2018-12-25_004857).
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http://dx.doi.org/10.1136/bmjopen-2020-040210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871690PMC
February 2021

The Importance of Understanding the Stages of COVID-19 in Treatment and Trials.

AIDS Rev 2021 02 8. Epub 2021 Feb 8.

Eastern Virginia Medical School|, Department of Internal Medicine, Chief, Pulmonary and Critical Care Medicine, Norfolk, VA, USA.

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.
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http://dx.doi.org/10.24875/AIDSRev.200001261DOI Listing
February 2021

Patient-reported olfactory recovery after SARS-CoV-2 infection: A 6-month follow-up study.

Int Forum Allergy Rhinol 2021 Feb 4. Epub 2021 Feb 4.

Department of Otolaryngology-Head and Neck Surgery, AOU Policlinico and University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.1002/alr.22775DOI Listing
February 2021

The role of antimicrobial stewardship in preventing KPC-producing Klebsiella pneumoniae.

J Antimicrob Chemother 2021 Jan;76(Supplement_1):i12-i18

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy.

Antimicrobial stewardship programmes are widely considered to be a core component of the response to the antimicrobial resistance threat. However, a positive impact of these interventions in terms of microbiological outcomes remains difficult to demonstrate, especially when focusing on specific resistant phenotypes. The first part of this review aims to explore the complex relationship between antibiotic exposure and resistance development in KPC-producing Klebsiella pneumoniae. In the second part we aim to summarize published examples of antimicrobial stewardship interventions intended to impact on the epidemiology of KPC-producing K. pneumoniae. For this purpose, a literature search was performed and seven studies were included in the review. Both restrictive and non-restrictive interventions were associated with an overall reduction in antibiotic consumption, and a decrease in carbapenem resistance rates was observed in five studies. The overall quality of the evidence was low, mainly due to the poor reporting of microbiological outcomes, lack of a control group and suboptimal study design. Although the link between antibiotic use and resistance development is supported by strong evidence, demonstrating the impact of antimicrobial stewardship interventions on microbiological outcomes remains difficult. Studies with adequate design and appropriate outcome measures are needed to further promote antimicrobial stewardship and elucidate which interventions are more successful for controlling the spread of KPC-producing K. pneumoniae.
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http://dx.doi.org/10.1093/jac/dkaa493DOI Listing
January 2021

Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naïve and -experienced, virologically-suppressed adults living with HIV-1.

HIV Res Clin Pract 2020 Dec 2;21(6):151-167. Epub 2021 Feb 2.

Janssen Research and Development LLC, Raritan, NJ, USA.

Background: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated in AMBER (treatment-naïve adults; NCT02431247) and EMERALD (treatment-experienced, virologically-suppressed adults; NCT02269917).

Objective: To describe a Week 96 pre-planned subgroup analysis of D/C/F/TAF arms by demographic characteristics (age ≤/>50 years, gender, black/non-black race), and baseline clinical characteristics (AMBER: viral load [VL], CD4 count, WHO clinical stage, HIV-1 subtype and antiretroviral resistance; EMERALD: prior virologic failure [VF], antiretroviral experience, screening boosted protease inhibitor [PI], and boosting agent).

Methods: Patients in D/C/F/TAF and control arms could continue on/switch to D/C/F/TAF in a single-arm, open-label extension phase after Week 48 until Week 96. Efficacy endpoints were percentage cumulative confirmed VL ≥50 copies/mL (virologic rebound; EMERALD), and VL <50 (virologic response), or ≥50 copies/mL (VF) (FDA snapshot; both trials).

Results: D/C/F/TAF demonstrated high Week 96 virologic responses (AMBER: 85% [308/362]; EMERALD: 91% [692/763]) and low VF rates (AMBER: 6% [20/362]; EMERALD: 1% [9/763]). In EMERALD, D/C/F/TAF showed low virologic rebound cumulative through Week 96 (3% [24/763]). Results were consistent across subgroups, including prior antiretroviral experience in EMERALD. No darunavir, primary PI, or tenofovir resistance-associated mutations were observed post-baseline. Study-drug-related serious adverse events (AEs) and AE-related discontinuations were <1% and 2%, respectively (both D/C/F/TAF arms), and similar across subgroups. eGFR and bone mineral density improved or were stable and lipids increased through Week 96 across demographic subgroups, with small changes in total-cholesterol/HDL-cholesterol ratio.

Conclusions: D/C/F/TAF was effective with a high barrier to resistance and bone/renal safety benefits, regardless of demographic or clinical characteristics for treatment-naïve and treatment-experienced, virologically-suppressed adults.
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http://dx.doi.org/10.1080/25787489.2020.1844520DOI Listing
December 2020

Virological response and resistance profile in highly treatment-experienced HIV-1-infected patients switching to dolutegravir plus boosted darunavir in clinical practice.

HIV Med 2021 Jan 21. Epub 2021 Jan 21.

Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.

Objectives: We evaluated the virological response and resistance profile in combined antiretroviral therapy (cART)-experienced HIV-1-infected patients starting a dual therapy with dolutegravir (DTG) and boosted darunavir (bDRV) for the first time.

Methods: Survival analyses were used to evaluate virological success (VS) and virological rebound (VR) in viraemic and virologically suppressed patients, respectively. Major resistance mutations (MRMs) and genotypic susceptibility score (GSS) were evaluated at baseline and after switch.

Results: Overall, 130 patients [62 (47.7%) viraemic; 68 (52.3%) virologically suppressed] were retrospectively analysed. At the moment of switch, 81.5% accumulated one or more MRM [protease inhibitor (PI), 35.7%; nucleoside(t)ide reverse transcriptase inhibitor (NRTI), 77.5%; non-NRTI, 69.0%; integrase inhibitor (INI), 10.1%), but 77.7% harboured strains fully susceptible to DTG + bDRV. In viraemic patients, the overall probability of VS by 12 months of treatment was 91.7%. In virologically suppressed patients, the overall probability of VR was 10.5% by 24 months after therapy start. Patients with previous time under virological suppression ≤ 6 months showed a higher VR probability compared with others (37.5% vs. 6.7%, P < 0.002). Among 13 non-responding patients for whom a genotypic resistance test result at failure was available, only two (15.4%) accumulated further resistance in integrase (Y143C/H/R; S147G and N155H) and protease (V32I, L33F, I54L).

Conclusions: In highly treatment-experienced patients, the use of dual therapy based on DTG + bDRV appears to be a very good regimen for switch therapy, with a high rate of virological control in both viraemic and virologically suppressed patients. Among non-responding patients, the selection of further resistance is a rare event.
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http://dx.doi.org/10.1111/hiv.13062DOI Listing
January 2021

Changes in central adipose tissue after switching to integrase inhibitors.

HIV Res Clin Pract 2020 Dec 18;21(6):168-173. Epub 2021 Jan 18.

University of Texas Health Sciences Center, Houston, TX, USA.

Treatment with integrase strand transfer inhibitors (INSTIs) has been associated with excess weight gain, however the long-term effect of INSTI-based regimens on adipose tissue (AT) compartments remains unknown. To evaluate the effect of switching to an INSTI on visceral (VAT) and subcutaneous (SAT) AT in virologically-suppressed adults with HIV. We performed a retrospective observational cohort study of ART experienced adults referred to the metabolic Clinic of the University of Modena and Reggio Emilia who had ≥2 assessments of body composition by abdominal computed tomography. An interrupted time series model with mixed-effect model incorporated was used to calculate VAT and SAT change rate, adjusting for smoking status, use of alcohol, and physical activity. A total of 698 patients were included: 156 who switched to an INSTI-based regimen and 542 who did not. After switch to INSTI, mean SAT area increased approximately 3-fold (before 0.27 vs after 0.73 cm/month;  = 0.011), and VAT area 7-fold (0.18 vs 1.30 cm/month;  < 0.001). Among PLWH on ART, both SAT and VAT gain accelerated after switching to an INSTI-based regimen. The associations between INSTIs and central adiposity require further investigation.
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http://dx.doi.org/10.1080/25787489.2020.1848131DOI Listing
December 2020

Heparin in COVID-19 Patients Is Associated with Reduced In-Hospital Mortality: the Multicenter Italian CORIST Study.

Authors:
Augusto Di Castelnuovo Simona Costanzo Andrea Antinori Nausicaa Berselli Lorenzo Blandi Marialaura Bonaccio Roberto Cauda Giovanni Guaraldi Lorenzo Menicanti Marco Mennuni Giustino Parruti Giuseppe Patti Francesca Santilli Carlo Signorelli Alessandra Vergori Pasquale Abete Walter Ageno Antonella Agodi Piergiuseppe Agostoni Luca Aiello Samir Al Moghazi Rosa Arboretti Marinella Astuto Filippo Aucella Greta Barbieri Alessandro Bartoloni Paolo Bonfanti Francesco Cacciatore Lucia Caiano Laura Carrozzi Antonio Cascio Arturo Ciccullo Antonella Cingolani Francesco Cipollone Claudia Colomba Crizia Colombo Francesca Crosta Gian Battista Danzi Damiano D'Ardes Katleen de Gaetano Donati Francesco Di Gennaro Giuseppe Di Tano Gianpiero D'Offizi Massimo Fantoni Francesco Maria Fusco Ivan Gentile Francesco Gianfagna Elvira Grandone Emauele Graziani Leonardo Grisafi Gabriella Guarnieri Giovanni Larizza Armando Leone Gloria Maccagni Ferruccio Madaro Stefano Maitan Sandro Mancarella Massimo Mapelli Riccardo Maragna Rossella Marcucci Giulio Maresca Silvia Marongiu Claudia Marotta Lorenzo Marra Franco Mastroianni Maria Mazzitelli Alessandro Mengozzi Francesco Menichetti Marianna Meschiari Jovana Milic Filippo Minutolo Beatrice Molena Arturo Montineri Cristina Mussini Maria Musso Daniela Niola Anna Odone Marco Olivieri Antonella Palimodde Roberta Parisi Emanuela Pasi Raffaele Pesavento Francesco Petri Biagio Pinchera Venerino Poletti Claudia Ravaglia Andrea Rognoni Marco Rossato Marianna Rossi Vincenzo Sangiovanni Carlo Sanrocco Laura Scorzolini Raffaella Sgariglia Paola Giustina Simeone Eleonora Taddei Carlo Torti Roberto Vettor Andrea Vianello Marco Vinceti Alexandra Virano Laura Vocciante Raffaele De Caterina Licia Iacoviello

Thromb Haemost 2021 Jan 7. Epub 2021 Jan 7.

Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Isernia, Italy.

Introduction:  A hypercoagulable condition was described in patients with coronavirus disease 2019 (COVID-19) and proposed as a possible pathogenic mechanism contributing to disease progression and lethality.

Aim:  We evaluated if in-hospital administration of heparin improved survival in a large cohort of Italian COVID-19 patients.

Methods:  In a retrospective observational study, 2,574 unselected patients hospitalized in 30 clinical centers in Italy from February 19, 2020 to June 5, 2020 with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection were analyzed. The primary endpoint in a time-to event analysis was in-hospital death, comparing patients who received heparin (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) with patients who did not. We used multivariable Cox proportional-hazards regression models with inverse probability for treatment weighting by propensity scores.

Results:  Out of 2,574 COVID-19 patients, 70.1% received heparin. LMWH was largely the most used formulation (99.5%). Death rates for patients receiving heparin or not were 7.4 and 14.0 per 1,000 person-days, respectively. After adjustment for propensity scores, we found a 40% lower risk of death in patients receiving heparin (hazard ratio = 0.60; 95% confidence interval: 0.49-0.74; E-value = 2.04). This association was particularly evident in patients with a higher severity of disease or strong coagulation activation.

Conclusion:  In-hospital heparin treatment was associated with a lower mortality, particularly in severely ill COVID-19 patients and in those with strong coagulation activation. The results from randomized clinical trials are eagerly awaited to provide clear-cut recommendations.
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http://dx.doi.org/10.1055/a-1347-6070DOI Listing
January 2021

Hypokalemia in Patients with COVID-19.

Clin Exp Nephrol 2021 Jan 4. Epub 2021 Jan 4.

Clinic of Infectious Diseases, University Hospital of Modena, Modena, Italy.

Background: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19.

Methods: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020.

Results: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3-3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36-4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08-3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228-1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170-1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222-1.047; P = 0.065) in our cohort of patients.

Conclusions: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.
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http://dx.doi.org/10.1007/s10157-020-01996-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781399PMC
January 2021

Virologic and immunologic outcomes of treatment with integrase inhibitors in a real-world setting: The RESPOND cohort consortium.

PLoS One 2020 31;15(12):e0243625. Epub 2020 Dec 31.

CHIP, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Objectives: To compare virologic and immunologic outcomes of integrase inhibitor (INSTI)-containing, contemporary boosted protease inhibitor (PI/b)-containing and non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens in a real-life setting.

Methods: Using logistic regression, virologic and immunologic outcomes of INSTI use were compared to outcomes of PI/b or NNRTI treatment 12 months after treatment start or switch, for participants in the RESPOND cohort consortium. A composite treatment outcome (cTO) was used, defining success as viral load (VL) <200 copies/mL and failure as at least one of: VL ≥200 copies/mL, unknown VL in the time window, any changes of antiretroviral therapy (ART) regimen, AIDS, or death. In addition, on-treatment analysis including only individuals with known VL and no regimen changes was performed. Favorable immunologic response was defined as a 25% increase in CD4 count or as reaching ≥750 CD4 cells/μL.

Results: Between January 2012 and January 2019, 13,703 (33.0% ART-naïve) individuals were included, of whom 7,147 started/switched to a regimen with an INSTI, 3,102 to a PI/b and 3,454 to an NNRTI-containing regimen. The main reason for cTO failure in all treatment groups were changes in ART regimen. Compared to INSTIs, the adjusted odds ratio (aOR) of cTO success was significantly lower for PI/b (0.74 [95% confidence interval, CI 0.67-0.82], p <0.001), but similar for NNRTIs (1.07 [CI 0.97-1.17], p = 0.11). On-treatment analysis and sensitivity analyses using a VL cut-off of 50 copies/mL were consistent. Compared to INSTIs, the aORs of a 25% increase in CD4 count were lower for NNRTIs (0.80 [CI 0.71-0.91], p<0.001) and PI/b (0.87 [CI 0.76-0.99], p = 0.04).

Conclusion: In this large analysis of a real-world population, cTO and on-treatment success were similar between INSTIs and NNRTIs, but lower for PI/b, though residual confounding cannot be fully excluded. Obtaining favorable immunologic outcomes were more likely for INSTIs than the other drug classes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243625PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774984PMC
February 2021

Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator.

Clin Microbiol Infect 2021 Jan 20. Epub 2021 Jan 20.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico of Modena, Modena, Italy; Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Italy.

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference.

Methods: This was a retrospective, observational cohort study among patients with severe COVID-19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death according to sex. Interaction was formally tested to compare the risk difference by sex in sub-populations. Mediation analysis with a binary endpoint IMV or death (yes/no) by day 28 of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted.

Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO/FiO (254 mmHg vs. 191 mmHg; p 0.023). By 28 days from admission, 49.2% (95% CI 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank p < 0.0001) and this amounted to a difference in terms of HR of 0.40 (0.26-0.63, p 0.0001). The area under the curve in C-reactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex.

Discussion: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. Specifically, CRP showed a predominant role to mediate the difference in risk by sex.
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http://dx.doi.org/10.1016/j.cmi.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816626PMC
January 2021

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

Clin Microbiol Infect 2021 Jan 18. 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
January 2021

Clinical outcomes of two-drug regimens vs. three-drug regimens in antiretroviral treatment-experienced people living with HIV.

Clin Infect Dis 2020 Dec 23. Epub 2020 Dec 23.

Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, UK.

Background: Limited data exist comparing clinical outcomes of two-drug regimens (2DRs) and three-drug regimens (3DRs) in people living with HIV.

Methods: Antiretroviral treatment-experienced individuals in RESPOND switching to a new 2DR or 3DR from 1/1/12-1/10/18 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression.

Results: Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median 52.6 years [interquartile range 46.7-59.0] vs 47.7 [39.7-54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%).There were 619 events during 27,159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU [95% CI 20.7-24.5]) on 3DRs, 79 (30.9/1000 PYFU [24.8-38.5]) on 2DRs. The most common events were death (7.5/1000 PYFU [95% CI 6.5-8.6]) and non-AIDS cancer (5.8/1000 PYFU [4.9-6.8]). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio: 0.92 [0.72-1.19]; p=0.53).

Conclusions: This is the first large, international cohort assessing clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes; further research on resistance barriers and long-term durability of 2DRs is needed.
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http://dx.doi.org/10.1093/cid/ciaa1878DOI Listing
December 2020

HIV care models during the COVID-19 era.

Clin Infect Dis 2020 Dec 19. Epub 2020 Dec 19.

Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain.

The COVID-19 pandemic is an unprecedented global challenge that substantially risks reversing the progress in ending HIV. At the same time, it may offer the opportunity for a new era of HIV management. This viewpoint presents the impact of COVID-19 on HIV care, including the Joint United Nations Programme on HIV/AIDS (UNAIDS) "three 90s" targets. It outlines how to enhance a patient-centered care approach, now known as the "fourth 90," by integrating face-to-face patient-physician and telemedicine encounters. It suggests a framework for prevention and treatment of multimorbidity and frailty, to achieve a good health-related quality of life and preserve intrinsic capacity in all people living with HIV.
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http://dx.doi.org/10.1093/cid/ciaa1864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799249PMC
December 2020

Immunomodulation for the management of severe SARS-CoV2 infections. State of the art and review of the literature.

Biochem Biophys Res Commun 2021 01 28;538:151-155. Epub 2020 Nov 28.

Department of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy.

This Mini Review of the literature aimed to assess the role of tocilizumab for the treatment of severe coronavirus disease 2019 (COVID-19). Based on the available scientific evidence, it is not clear to date what is the best therapeutic strategy for the treatment of COVID-19. Since SARS-CoV-2 infection stimulates a vigorous proinflammatory response and may cause the so-called "cytokine storm", immunomodulator drugs have been investigated as potential treatment for severe COVID-19 pneumonia. Among immunomodulators, tocilizumab, a recombinant humanized monoclonal antibody directed against IL-6 receptor, seems to be promising. An increasing number of clinical trials are exploring the role of tocilizumab in COVID-19, focusing on outcomes like mortality, risk of intensive care unit admission and the need for mechanical ventilation. At the moment, there is no conclusive evidence that tocilizumab would be proper outright in all patients with COVID-19 pneumonia, but some studies suggest that its use may be beneficial in selected categories of patients.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699161PMC
January 2021

NLRP3 and IL-1β Gene Expression Is Elevated in Monocytes From HIV-Treated Patients With Neurocognitive Disorders.

J Acquir Immune Defic Syndr 2021 Apr;86(4):496-499

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

Background: Systemic immune activation and inflammation in chronic HIV infection are driving factors of non-AIDS-related events, including neurocognitive impairment. The role of inflammasome in monocytes from patients with HIV infection has been extensively studied, but its association with the extent of neurocognitive dysfunction has been poorly investigated.

Methods: We enrolled 79 HIV-positive patients; 44 with varying levels of HIV-associated neurocognitive disorder (HAND) and 35 without and 8 healthy donors. HAND subtypes included asymptomatic neurocognitive impairment (asymptomatic neurocognitive impairment; n = 19), mild neurocognitive disorder (MND; n = 17), and HIV-associated dementia (n = 8). We quantified plasmatic concentrations of proinflammatory cytokines (TNF-α, IL-6, IL-17A, IL-1β, and IFN-γ) for all HIV patients, and the mRNA expression of genes involved in the inflammasome activity (NLRP3, PYCARD, NAIP, AIM2, IL-1β, and IL-18) in monocytes of a subgroup of 28 HIV patients and 8 healthy donors.

Results: HIV patients' plasma concentrations of IFN-γ, IL-1β, and IL-17A were undetectable. Levels of TNF-α and IL-6 were similar among the HIV patient groups. A trend toward an increased expression of inflammasome genes according to neurocognitive disorder severity was observed. Of note, the NLRP3 mRNA relative expression was higher in MND compared with other groups, and IL-1β was lower in MND than HIV-associated dementia patients.

Conclusions: Changes in inflammasome components in circulating monocytes according to different HAND severity suggest that NLRP3 may be a possible biomarker or target to better understand and treat the link between systemic inflammation and neurocognitive impairment in HIV infection.
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http://dx.doi.org/10.1097/QAI.0000000000002588DOI Listing
April 2021

Beyond Italian guidelines in the management of HIV-positive patient.

Infez Med 2020 Nov;28(4):587-596

Department of Laboratory Medicine, ASST Niguarda Hospital, Milan, Italy.

Although AIDS/HIV infection and related deaths have significantly decreased in Italy in recent years, new problems have made it more challenging to manage the disease. To overcome the new hurdles, the Italian National Plan of Interventions against HIV and AIDS was recently issued by the National Health Authorities, and the Italian Guidelines (GL) for diagnosis, therapy and management of HIV-1 infection were subsequently drafted by the Italian Society of Infectious and Tropical Diseases (SIMIT). Although the GLs provide clear recommendations, they are open to personal interpretation depending on the experience and/or background of individual healthcare professionals. To minimize the interpretative variability, eight residential meetings were organized in Italy in 2019 to promote a multidisciplinary approach and discuss specific HIV-associated conditions, such as cardiovascular or neuro-psychological comorbidities, advanced stage of infection, and high CD4 cell counts. To undertake this educational program, the GLs were simplified into key steps by creating ad hoc decisional algorithms, and an innovative multimedia technology was used during the meetings to collect and summarize individual opinions up to the final statements. For HIV patients with cardiovascular diseases, "CV risk factor identification" and "change of patients' lifestyle" were the most commonly shared approaches by all healthcare professionals, regardless of individual attitudes. Among HIV individuals with neurocognitive and psychological comorbidities, "more neurocognitive tests", "better customization of antiretroviral therapy (ART)", and "assessment of psychological symptoms" were the most frequently identified options to carry out. Advanced HIV infection and low CD4 cell count being a particularly serious condition burdened by high mortality, almost all specialists oriented their opinion toward a prompt and scrupulous clinical evaluation to be performed just before and immediately after the start of ART. Finally, the most pursued recommendations in patients with acute HIV infection and high CD4 cell count were the achievement of a "prompt diagnosis" and "start of well-shaped ART", as the most appropriate means to keep the viral load as low as possible. Undoubtedly, despite negligible discrepancies in individual interpretation among specialists, this nationwide educational program was able to capture local differences, but to guarantee at the same time a constant alignment of individual specialists towards the Italian clinical practice GLs. Different priorities in the daily management of the four HIV-1 subpopulations highlighted during the meetings reflect the presence of different regional health policies nationwide, in turn generating different healthcare offers. This program offered state-of-the-art management of four widely represented subpopulations of HIV-1 patients.
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November 2020

Epidemiology and Risk Factors Associated With Mortality in Consecutive Patients With Bacterial Bloodstream Infection: Impact of MDR and XDR Bacteria.

Open Forum Infect Dis 2020 Nov 30;7(11):ofaa461. Epub 2020 Sep 30.

Department of Infectious Diseases, Azienda Ospedaliero-Universitaria "Policlinico of Modena," Modena, Italy.

Background:  Mortality related to bloodstream infections (BSIs) is high. The epidemiology of BSIs is changing due to the increase in multidrug resistance, and it is unclear whether the presence of multidrug-resistant (MDR) organisms, per se, is an independent risk factor for mortality. Our objectives were, first, to describe the epidemiology and outcome of BSIs and, second, to determine the risk factors associated with mortality among patients with BSI.

Methods:  This research used a single-center retrospective observational study design. Patients were identified through microbiological reports. Data on medical history, clinical condition, bacteria, antimicrobial therapy, and mortality were collected. The primary outcome was crude mortality at 30 days. The relationships between mortality and demographic, clinical, and microbiological variables were analyzed by multivariate analysis.

Results:  A total of 1049 inpatients were included. MDR bacteria were isolated in 27.83% of patients, where 2.14% corresponded to an extremely drug-resistant (XDR) isolate. The crude mortality rates at days 7, 30, and 90 were 12.11%, 25.17%, and 36.13%, respectively. Pitt score >2, lung and abdomen as site of infection, and XDR were independent risk factors for 7-, 30-, and 90-day mortality. Charlson score >4, carbapenem-resistant , and XDR were independent risk factors for 30- and 90-day mortality. Infection by XDR gram-negative bacteria, Charlson score >4, and immunosuppression were independent risk factors for mortality in patients who were stable at the time of BSI.

Conclusions:  BSI is an event with an extreme impact on mortality. Patients with severe clinical condition are at higher risk of death. The presence of XDR gram-negative bacteria in blood is strongly and independently associated with patient death.
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http://dx.doi.org/10.1093/ofid/ofaa461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652098PMC
November 2020

Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia-Challenges, strengths, and opportunities in a global health emergency.

PLoS One 2020 12;15(11):e0239172. Epub 2020 Nov 12.

Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Aims: The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia.

Methods: This was an observational prospective study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients' medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO2/FiO2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome.

Results: A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth "boosted mixed model" included 20 variables was selected from the model 3, achieved the best predictive performance (AUC = 0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example.

Conclusion: This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239172PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660476PMC
November 2020

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

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

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

Background: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients.

Methods: A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival.

Results: In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6-24.0, P = 0.52) and 22.4% (97.5% CI: 17.2-28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline.

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

Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia.

EMBO Mol Med 2020 12 5;12(12):e13001. Epub 2020 Nov 5.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.
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http://dx.doi.org/10.15252/emmm.202013001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645870PMC
December 2020

Ceftazidime/avibactam and ceftolozane/tazobactam for the treatment of extensively drug-resistant Pseudomonas aeruginosa post-neurosurgical infections: three cases and a review of the literature.

Infection 2020 Oct 19. Epub 2020 Oct 19.

Department of Infectious Diseases, University of Modena and Reggio Emilia, Modena, Italy.

Purpose: Post-neurosurgical infection caused by extensively drug resistant Pseudomonas aeruginosa (XDR-PA) are becoming a matter of great concern due to limited therapeutic options. Although not approved for these indications, the new BetaLactam-BetaLactamase Inhibitor combinations (BLBLIs) could represent a valid salvage treatment. We describe one nosocomial meningitis and two cervical osteomyelitis due to an XDR-PA who were treated with ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) and review the literature.

Methods: The first and the third patients developed an osteomyelitis following cervical stabilization surgery due to an XDR-PA. Although the first patient started treatment with a high dose of C/T, resistance to C/T occurred, so therapy was switched to CZA plus aztreonam. The third patient switched to aztreonam plus CZA due to development of acute kidney injury during therapy with colistin. The second patient had an XDR-PA meningitis following the insertion of an external ventricular catheter and he was treated with C/T plus meropenem and amikacin.

Results: All three cases reported were successfully conservatively treated thanks to the use of the new BLBLIs with different combinations. Only few experiences demonstrated an equally favorable outcome: one patient treated with C/T plus fosfomycin for otogenic meningitis caused by an XDR-PA and another case of XDR-PA post-surgical meningitis with CZA in combination with colistin. Finally, the combination of CZA plus aztreonam has proven to be effective on XDR-PA only in limited mostly in vitro studies.

Conclusion: These recently developed antibiotics, C/T and CZA are promising and complementary therapy options against post-neurosurgical hard-to-treat P. aeruginosa infections. Further prospective real-life studies are required to validate these findings in this special setting.
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http://dx.doi.org/10.1007/s15010-020-01539-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569357PMC
October 2020

TOCIVID-19 - A multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia. Study protocol.

Contemp Clin Trials 2020 11 6;98:106165. Epub 2020 Oct 6.

Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy. Electronic address:

Background: Pneumonia is the most frequent complication of COVID-19, due to an aberrant host immune response that is associated with an acute respiratory distress syndrome, and, in most critical patients, with a "cytokine storm". IL-6 might play a key role in the cytokine storm and might be a potential target to treat severe and critical COVID-19. Tocilizumab is a recombinant humanized monoclonal antibody, directed against IL-6 receptor.

Methods: This multicentre study project includes a single-arm phase 2 study and a further parallel cohort, enrolling hospitalized patients with COVID-19 pneumonia and oxygen saturation at rest in ambient air ≤93% or requiring respiratory support. Patients receive tocilizumab 8 mg/kg (up to 800 mg) as one intravenous administration. A second administration (same dose) after 12 h is optional. Two-week and one-month lethality rates are the co-primary endpoints. Sample size planned for the phase 2 study is 330 patients. The parallel cohort will include patients who cannot enter the phase 2 study because being intubated from more than 24 h, or having already received tocilizumab, or the phase 2 study has reached sample size. Primary analysis will include patients enrolled in the phase 2 study. Results of the primary analysis will be validated in the prospective cohort of patients consecutively registered after phase 2 closure from March 20 to March 24, who were potentially eligible for the phase 2 study.

Conclusion: This trial aims to verify the safety and efficacy of tocilizumab in the Italian population with COVID-19 pneumonia and respiratory impairment. EudraCT Number: 2020-001110-38; Clinicaltrials.gov ID NCT04317092.
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http://dx.doi.org/10.1016/j.cct.2020.106165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536129PMC
November 2020

Liver steatosis and nonalcoholic fatty liver disease with fibrosis are predictors of frailty in people living with HIV.

AIDS 2020 11;34(13):1915-1921

Modena HIV Metabolic Clinic.

Objective: The aim was to investigate the contribution of liver steatosis and significant fibrosis alone and in association [nonalcoholic fatty liver disease (NAFLD) with fibrosis] to frailty as a measure of biological age in people living with HIV (PLWH).

Design: This was a cross-sectional study of consecutive patients attending Modena HIV Metabolic Clinic in 2018-2019.

Methods: Patients with hazardous alcohol intake and viral hepatitis coinfection were excluded. Liver steatosis was diagnosed by controlled attenuation parameter (CAP), while liver fibrosis was diagnosed by liver stiffness measurement (LSM). NAFLD was defined as presence of liver steatosis (CAP ≥248 dB/m), while significant liver fibrosis or cirrhosis (stage ≥F2) as LSM at least 7.1 kPa. Frailty was assessed using a 36-Item frailty index. Logistic regression was used to explore predictors of frailty using steatosis and fibrosis as covariates.

Results: We analysed 707 PLWH (mean age 53.5 years, 76.2% men, median CD4 cell count 700 cells/μl, 98.7% with undetectable HIV RNA). NAFLD with fibrosis was present in 10.2%; 18.9 and 3.9% of patients were classified as frail and most-frail, respectively. Univariate analysis demonstrated that neurocognitive impairment [odds ratio (OR) = 5.1, 1.6-15], vitamin D insufficiency (OR = 1.94, 1.2-3.2), obesity (OR = 8.1, 4.4-14.6), diabetes (OR = 3.2, 1.9-5.6), metabolic syndrome (OR = 2.41, 1.47-3.95) and osteoporosis (OR = 0.37, 0.16-0.76) were significantly associated with NAFLD with fibrosis. Predictors of frailty index included steatosis (OR = 2.1, 1.3-3.5), fibrosis (OR = 2, 1-3.7), NAFLD with fibrosis (OR = 9.2, 5.2-16.8), diabetes (OR = 1.7, 1-2.7) and multimorbidity (OR = 2.5, 1.5-4).

Conclusion: Liver steatosis and NAFLD with fibrosis were associated with frailty. NAFLD with fibrosis exceeded multimorbidity in the prediction of frailty, suggesting the former as an indicator of metabolic age in PLWH.
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http://dx.doi.org/10.1097/QAD.0000000000002650DOI Listing
November 2020