Monoclonal antibodies against SARS-CoV-2 to prevent COVID-19 worsening in a large multicenter cohort.

Objective: Monoclonal antibodies (mAbs) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reduced Coronavirus Disease 2019 (COVID-19) hospitalizations in people at risk of clinical worsening. Real-world descriptions are limited. Methods: CONDIVIDIAMO, a two-year multicenter observational study, consecutively enrolled SARS-CoV-2 outpatients with ≥1 risk factor for COVID-19 progression receiving mAbs. Demographic data, underlying medical condition, type of mAbs combination received, duration of symptoms before mAbs administration, COVID-19 vaccination history, were collected upon enrolment and centrally recorded. Data on outcomes (hospitalizations, reasons of hospitalization, deaths) were prospectively collected. The primary endpoint was the rate of hospitalization or death in a 28-day follow-up, whichever occurred first; subjects were censored at the day of last follow-up or up to 28 days. The Kaplan-Meier method was used to estimate the incidence rate curve in time. The Cox regression model was used to assess potential risk factors for unfavorable outcome. Results were shown as hazard ratio (HR) along with the corresponding 95 % Confidence Interval (95%CI). Results: Among 1534 subjects (median [interquartile range, IQR] age 66.5 [52.4-74.9] years, 693 [45.2 %] women), 632 (41.2 %) received bamlanivimab ± etesevimab, 209 (13.6 %) casirivimab/imdevimab, 586 (38.2 %) sotrovimab, 107 (7.0 %) tixagevimab/cilgavimab. After 28-day follow-up, 87/1534 (5.6 %, 95%CI: 4.4%-6.8 %) met the primary outcome (85 hospitalizations, 2 deaths). Hospitalizations for COVID-19 (52, 3.4 %) occurred earlier than for other reasons (33, 2.1 %), after a median (IQR) of 3.5 (1-7) versus 8 (3-15) days (p = 0.006) from mAbs administration.In a multivariable Cox regression model, factors independently associated with increased hospitalization risk were age (hazard ratio [HR] 1.02, 95%CI 1.00-1.03, p = 0.021), immunodeficiency (HR 1.78, 95%CI 1.11-2.85, p = 0.017), pre-Omicron calendar period (HR 1.66, 95%CI 1.02-2.69, p = 0.041). Conclusions: MAbs real-world data over a 2-year changing pandemic landscape showed the feasibility of the intervention, although the hospitalization rate was not negligible. Immunosuppressed subjects remain more at risk of clinical worsening.

Cefiderocol-Based Regimen for Acinetobacter NDM-1 Outbreak.

Variable outcomes have been reported with cefiderocol in infections due to carbapenem-resistant Acinetobacter baumannii (CRAB). Nonetheless, it may be the only option for metallo-beta-lactamase-producing strains. We describe an outbreak of NDM-CRAB infections treated with cefiderocol. Thirty-eight patients were colonized and/or infected. Thirteen patients developed a systemic infection. A clinical cure was achieved in 10 (83%) patients, one VAP and 9 BSIs, at day 7. In vitro, the activity of cefiderocol does not appear to match in vivo effectiveness using currently available commercial tests. Despite high clinical cures, overall mortality remains high in severely ill patients. Cefiderocol may be considered in this specific setting, though the implementation of susceptibility tests and infection control measures is mandatory.

Cerebral Infectious Opportunistic Lesions in a Patient with Acute Myeloid Leukaemia: The Challenge of Diagnosis and Clinical Management.

Central nervous system (CNS) lesions, especially invasive fungal diseases (IFDs), in immunocompromised patients pose a great challenge in diagnosis and treatment. We report the case of a 48-year-old man with acute myeloid leukaemia and probable pulmonary aspergillosis, who developed hyposthenia of the left upper limb, after achieving leukaemia remission and while on voriconazole. Magnetic resonance imaging (MRI) showed oedematous CNS lesions with a haemorrhagic component in the right hemisphere with lepto-meningitis. After 2 weeks of antibiotics and amphotericin-B, brain biopsy revealed chronic inflammation with abscess and necrosis, while cultures were negative. Clinical recovery was attained, he was discharged on isavuconazole and allogeneic transplant was postponed, introducing azacitidine as a maintenance therapy. After initial improvement, MRI worsened; brain biopsy was repeated, showing similar histology; and 16S metagenomics sequencing analysis was positive (Veilonella, Pseudomonas). Despite 1 month of meropenem, MRI did not improve. The computer tomography and PET scan excluded extra-cranial infectious-inflammatory sites, and auto-immune genesis (sarcoidosis, histiocytosis, CNS vasculitis) was deemed unlikely due to the histological findings and unilateral lesions. We hypothesised possible IFD with peri-lesion inflammation and methyl-prednisolone was successfully introduced. Steroid tapering is ongoing and isavuconazole discontinuation is planned with close follow-up. In conclusion, the management of CNS complications in immunocompromised patients needs an interdisciplinary approach.

Meropenem-Vaborbactam for the Treatment of Post-Neurosurgical Meningitis Caused by KPC Producer Klebsiella Pneumoniae: A Case Report and Review of the Literature.

Meningitis and ventriculitis, due to carbapenem-resistant Enterobacterales, are frequently associated with significant morbidity and mortality. In the case of multi-drug-resistant pathogens, it is necessary to consider the limited susceptibility profile as well as the penetration of the antimicrobials into the brain. Limited data are available regarding the treatment of central nervous system infections caused by carbapenem-resistant Enterobacterales. We report a study of a patient treated with meropenem-vaborbactam in the case of post-neurosurgical meningitis due to carbapenemase-producing Klebsiella pneumoniae (CPKP).

A case of chronic bacterial prostatitis due to Mycoplasma genitalium.

Mycoplasma genitalium (MG) is a common cause of non-gonococcal urethritis, but a role in acute or chronic prostatitis has not been described. We describe the case of a 42-year-old man with recurrent urinary tract infections since 2018 who developed chronic prostatitis despite several and prolonged antibiotic courses. Multiparametric prostatic magnetic resonance showed peripheral inflammatory alterations. A 4-glass Meares-Stamey test detected MG in the third voided bladder (VB3) sample. Moxifloxacin 400 mg daily for 28 days resulted in sustained clinical and microbiological cure.

Effectiveness and Safety of Remdesivir in Treating Hospitalised Patients with COVID-19: A Propensity Score Analysis of Real-Life Data from a Monocentric Observational Study in Times of Health Emergency.

BACKGROUND AND OBJECTIVES: Remdesivir is an antiviral agent, which was shown to be safe and effective in treating early COVID-19, but its favourable impact in hospitalised patients with non-critical disease is still under investigation. The present study aimed to assess the effectiveness and safety of remdesivir as a treatment for hospitalised patients with COVID-19 by a propensity score analysis of observational data. METHODS: In this monocentric retrospective cohort study, the effectiveness and safety of a 5-day course of remdesivir (200 mg intravenously at Day 1, then 100 mg from Days 2-5) in association with the standard of care were assessed in comparison with the standard of care only. The primary endpoint was the proportion of recovery on Day 14. RESULTS: Of 3662 eligible inpatients who tested positive for the severe acute respiratory syndrome coronavirus 2 genome by nasopharyngeal swab at admission, 861 (24%) non-critical patients were included in a propensity score analysis and 281 (33%) were exposed to remdesivir. In total, 242/281 (86.1%) and 435/580 (75.0%) patients recovered in exposed and non-exposed, respectively, with a relative improvement of 11.1% (95% CI + 5.8 to 16.5%; unadjusted odds ratio: 2.07, 95% CI 1.40-3.05, p = 0.0001; after adjustment by propensity score weighting, odds ratio: 1.92, 95% CI 1.30-2.83, p = 0.001). In treated patients, 1 (0.03%) anaphylactic reaction and 1 (0.03%) acute reaction during drug injection were reported, and 24 (8.5%) patients stopped the treatment due to adverse reactions. No significant differences were found with respect to the secondary efficacy endpoints (in-hospital all-cause death, need for intensive care treatments, clinical improvement score at Day 28) and safety endpoints (any and serious adverse reactions). CONCLUSION: A 5-day course of remdesivir in association with the standard of care effectively promoted recovery from COVID-19 among non-critical in-hospital patients and had an acceptable safety profile.

The effect of antithrombotic treatment on mortality in patients with acute infection: A meta-analysis of randomized clinical trials.

BACKGROUND AND AIMS: Acute infections cause relevant activation of innate immunity and inflammatory cascade. An excessive response against pathogens has been proved to trigger the pathophysiological process of thrombo-inflammation. Nevertheless, an association between the use of antithrombotic agents and the outcome of critically ill patients with infectious diseases is lacking. The aim of this meta-analysis is to determine the impact of antithrombotic treatment on survival of patients with acute infective disease. METHODS: MEDLINE, Embase, Cinahl, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched from inception to March 2021. We included randomized controlled trials (RCTs) that evaluated any antithrombotic agent in patients with infectious diseases other than COVID-19. Two authors independently performed study selection, data extraction and risk of bias evaluation. The primary outcome was all-cause mortality. Summary estimates for mortality were calculated using the inverse-variance random-effects method. RESULTS: A total of 16,588 patients participating in 18 RCTs were included, of whom 2141 died. Four trials evaluated therapeutic-dose anticoagulation, 1 trial prophylactic-dose anticoagulation, 4 trials aspirin, and 9 trials other antithrombotic agents. Overall, the use of antithrombotic agents was not associated with all-cause mortality (relative risk 0.96; 95% confidence interval, 0.90-1.03). CONCLUSIONS: The use of antithrombotics is not associated with all-cause mortality in patients with infectious disease other than COVID-19. Complex pathophysiological interplays between inflammatory and thrombotic pathways may explain these results and need further investigation. REGISTRATION: PROSPERO, CRD42021241182.

Similar survival but higher and delayed hepatocellular carcinoma recurrence in HIV-positive compared to negative cirrhotics undergoing liver transplantation.

BACKGROUND: Liver transplantation (LT) represents the best therapeutic option for hepatocellular carcinoma (HCC) and end-stage liver disease (ESLD). Although HIV infection does not seem to lower survival rates, HCV and HCC recurrence appear more harmful. AIMS: To compare the overall survival after LT; evaluate the impact of anti-HCV direct-acting agents (DAA); assess the rate of HCC recurrence in HIV-positive and negative patients. METHODS: Subjects with HCV/HBV infection who underwent LT for HCC or ESLD from 2012 to 2019 were retrospectively evaluated. RESULTS: Study population included 299 individuals, 31 (10.4%) were HIV-positive. Overall mortality was similar (16.1% versus 19.0%, p = 0.695). HCC recurrence was observed in 6 HIV-positive (19.4%) and in 17 negative subjects (6.3%, p = 0.022). Time to relapse was 831 days in HIV-positive and 315 days in negative patients (p = 0.046). Cox model found a significant role for HIV in univariate analysis but, after adjusting for variables, extra-hepatic tumor was the only factor associated to recurrence (aHR 56.379, p < 0.001). CONCLUSIONS: Post-LT survival improved after DAA availability and HIV has no impact on mortality. A higher and delayed rate of HCC recurrence was observed in co-infected individuals: surveillance protocols should be strengthened along time in this population.

SARS-CoV-2 RNA in plasma samples of COVID-19 affected individuals: a cross-sectional proof-of-concept study.

BACKGROUND: Recent studies showed that plasma SARS-CoV-2 RNA seems to be associated with worse COVID-19 outcome. However, whether specific population can be at higher risk of viremia are to date unexplored. METHODS: This cross-sectional proof-of-concept study included 41 SARS-CoV-2-positive adult individuals (six affected by haematological malignancies) hospitalized at two major hospital in Milan, for those demographic, clinical and laboratory data were available. SARS-CoV-2 load was quantified by ddPCR in paired plasma and respiratory samples. To assess significant differences between patients with and patients without viremia, Fisher exact test and Wilcoxon test were used for categorical and continuous variables, respectively. RESULTS: Plasma SARS-CoV-2 RNA was found in 8 patients (19.5%), with a median (IQR) value of 694 (209-1023) copies/mL. Viremic patients were characterized by an higher mortality rate (50.0% vs 9.1%; p = 0.018) respect to patients without viremia. Viremic patients were more frequently affected by haematological malignancies (62.5% vs. 3.0%; p < 0.001), and had higher viral load in respiratory samples (9,404,000 [586,060-10,000,000] vs 1560 [312-25,160] copies/mL; p = 0.002). CONCLUSIONS: Even if based on a small sample population, this proof-of-concept study poses the basis for an early identification of patients at higher risk of SARS-CoV-2 viremia, and therefore likely to develop severe COVID-19, and supports the need of a quantitative viral load determination in blood and respiratory samples of haematologic patients with COVID-19 in order to predict prognosis and consequently to help their further management.

Neurological manifestations in patients hospitalized with COVID-19: A retrospective analysis from a large cohort in Northern Italy.

SARS-CoV2 infection is a systemic disease that may involve multiple organs, including the central nervous system (CNS). Aims of our study are to describe prevalence and clinical features of neurological manifestations, mortality and hospital discharge in subjects hospitalized with COVID-19. All individuals admitted for to our hospital COVID-19 were retrospectively included. Patients were classified according to the symptoms at hospital entry in (1) isolated respiratory, (2) combined respiratory and neurologic, (3) isolated neurologic and (4) stroke manifestations. Descriptive statistics and nonparametric tests to compare the groups were calculated. Kaplan Meier probability curves and multivariable Cox regression models for survival and hospital discharge were applied. The analysis included 901 patients: 42.6% showed a severe or critical disease with an overall mortality of 21.2%. At least one neurological symptom or disease was observed in 30.2% of subjects ranging from dysgeusia/anosmia (9.1%) to postinfective diseases (0.8%). Patients with respiratory symptoms experienced a more severe disease and a higher in-hospital mortality compared to those who showed only neurologic symptoms. Kaplan Meier estimates displayed a statistically significant different survival among groups (p = 0.003): subjects with stroke had the worst. After adjusting for risk factors such as age, sex and comorbidity, individuals with isolated neurologic manifestations exhibited a better survival (aHR 0.398, 95% CI [0.206, 0.769], p = 0.006). Neurologic manifestations in COVID-19 are common but heterogeneous and mortality in subjects with isolated neurologic manifestations seems lower than in those with respiratory symptoms.

Effectiveness of infection-containment measures on SARS-CoV-2 seroprevalence and circulation from May to July 2020, in Milan, Italy.

OBJECTIVE: Through a hospital-based SARS-CoV-2 molecular and serological screening, we evaluated the effectiveness of two months of lockdown and two of surveillance, in Milan, Lombardy, the first to be overwhelmed by COVID-19 pandemics during March-April 2020. METHODS: All subjects presenting at the major hospital of Milan from May-11 to July-5, 2020, underwent a serological screening by chemiluminescent assays. Those admitted were further tested by RT-PCR. RESULTS: The cumulative anti-N IgG seroprevalence in the 2753 subjects analyzed was of 5.1% (95%CI = 4.3%-6.0%), with a peak of 8.4% (6.1%-11.4%) 60-63 days since the peak of diagnoses (March-20). 31/106 (29.2%) anti-N reactive subjects had anti-S1/S2 titers >80 AU/mL. Being tested from May-18 to June-5, or residing in the provinces with higher SARS-CoV-2 circulation, were positively and independently associated with anti-N IgG reactivity (OR [95%CI]: 2.179[1.455-3.264] and 3.127[1.18-8.29], respectively). In the 18 RT-PCR positive, symptomatic subjects, anti-N seroprevalence was 33.3% (95% CI: 14.8%-56.3%). CONCLUSION: SARS-CoV-2 seroprevalence in Milan is low, and in a downward trend after only 60-63 days since the peak of diagnoses. Italian confinement measures were effective, but the risk of contagion remains concrete. In hospital-settings, the performance of molecular and serological screenings upon admission remains highly advisable.

Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis.

BACKGROUND: As the novel SARS-CoV-2 pandemic occurred, no specific treatment was yet available. Inflammatory response secondary to viral infection might be the driver of severe diseases. We report the safety and efficacy (in terms of overall survival and hospital discharge) of the anti-IL6 tocilizumab (TCZ) in subjects with COVID-19. METHODS: This retrospective, single-center analysis included all the patients consecutively admitted to our Hospital with severe or critical COVID-19 who started TCZ treatment from March 13th to April 03rd, 2020. A 1:2 matching to patients not treated with TCZ was performed according to age, sex, severity of disease, P/F, Charlson Comorbidity Index and length of time between symptoms onset and hospital admittance. Descriptive statistics and non-parametric tests to compare the groups were applied. Kaplan Meier probability curves and Cox regression models for survival, hospital discharge and orotracheal intubation were used. RESULTS: Seventy-four patients treated with TCZ were matched with 148 matched controls. They were mainly males (81.5%), Caucasian (82.0%) and with a median age of 59 years. The majority (69.8%) showed critical stage COVID-19 disease. TCZ use was associated with a better overall survival (HR 0.499 [95% CI 0.262-0.952], p = 0.035) compared to controls but with a longer hospital stay (HR 1.658 [95% CI 1.088-2.524], p = 0.019) mainly due to biochemical, respiratory and infectious adverse events. DISCUSSION: TCZ use resulted potentially effective on COVID-19 in terms of overall survival. Caution is warranted given the potential occurrence of adverse events. FINANCIAL SUPPORT: Some of the tocilizumab doses used in the subjects included in this analysis were provided by the "Multicenter study on the efficacy and tolerability of tocilizumab in the treatment of patients with COVID-19 pneumonia" (EudraCT Number: 2020-001110-38) supported by the Italian National Agency for Drugs (AIFA). No specific funding support was planned for study design, data collection and analysis and manuscript writing of this paper.