Clinical characteristics, management and health related quality of life in young to middle age adults with COVID-19.

BACKGROUND: The outbreak of COVID-19 has rapidly spread to Italy, including Pesaro-Urbino province. Data on young to middle age adults with COVID-19 are lacking. We report the characteristics, management and health-related quality of life (HRQoL) in patients with COVID-19 aging ≤50 years. METHODS: A retrospective analysis was performed in all patients ≤50 years with a confirmed diagnosis of COVID-19 admitted to Emergency department (ED) of San Salvatore Hospital in Pesaro from February 28th to April 8th, 2020. Data were collected from electronical medical records. HRQoL was investigated after 1 month from hospital discharge using the SF-36 questionnaire. Outcomes were evaluated between hospitalized and not hospitalized patients. RESULTS: Among 673 patients admitted to the ED and diagnosed with COVID-19, 104 (15%) were ≤ 50 years old: 74% were discharged at home within 48 h, 26% were hospitalized. Fever occurred in 90% of the cases followed by cough (56%) and dyspnoea (34%). The most frequent coexisting conditions were hypertension (11%), thyroid dysfunction (8%) and neurological and/or mental disorders [NMDs] (6%). Mean BMI was 27. Hypokalaemia and NMDs were significantly more common in patients who underwent mechanical ventilation. Regardless of hospitalization, there was an impairment in both the physical and mental functioning. CONCLUSIONS: Overweight and hypertension are frequent conditions in young to middle age adults with COVID-19. Hypokalaemia and NMDs are commonly associated with progressive disease. A significant impact on HRQoL in the early stage of post-discharge is common in this population.

Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU.

BACKGROUND: Remdesivir is a prodrug with in vitro activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Its clinical efficacy in patients with COVID-19 under mechanical ventilation remains to be evaluated. METHODS: This study includes patients under mechanical ventilation with confirmed SARS-CoV-2 infection admitted to the ICU of Pesaro hospital between 29 February and 20 March 2020. During this period, remdesivir was provided on a compassionate use basis. Clinical characteristics and outcome of patients treated with remdesivir were collected retrospectively and compared with those of patients hospitalized in the same time period. RESULTS: A total of 51 patients were considered, of which 25 were treated with remdesivir. The median (IQR) age was 67 (59-75.5) years, 92% were men and symptom onset was 10 (8-12) days before admission to ICU. At baseline, there was no significant difference in demographic characteristics, comorbidities and laboratory values between patients treated and not treated with remdesivir. Median follow-up was 52 (46-57) days. Kaplan-Meier curves showed significantly lower mortality among patients who had been treated with remdesivir (56% versus 92%, P < 0.001). Cox regression analysis showed that the Charlson Comorbidity Index was the only factor that had a significant association with higher mortality (OR 1.184; 95% CI 1.027-1.365; P = 0.020), while the use of remdesivir was associated with better survival (OR 3.506; 95% CI 1.768-6.954; P < 0.001). CONCLUSIONS: In this study the mortality rate of patients with COVID-19 under mechanical ventilation is confirmed to be high. The use of remdesivir was associated with a significant beneficial effect on survival.

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication.

BACKGROUND: The persistence of HIV-1 in reservoir cells is one of the major obstacles to eradicating the virus in infected individuals receiving combination antiretroviral therapy (ART). HIV-1 persists in infected cells as a stable integrated genome and more labile unintegrated DNA (uDNA), which includes linear, 1-LTR and 2-LTR circular DNA. 2-LTR circle DNA, although less abundant, is considered a surrogate marker of recent infection events and is currently used instead of the other unintegrated species as a diagnostic tool. This pilot study aimed to investigate how to best achieve the measurement of uDNA. METHODS: A comparative analysis of two qPCR-based methods (U-assay and 2-LTR assay) was performed on the blood of 12 ART-naïve, 14 viremic and 29 aviremic On-ART patients and 20 untreated spontaneous controllers (HIC), sampled at a single time point. RESULTS: The U-assay, which quantified all unintegrated DNA species, showed greater sensitivity than the 2-LTR assay (up to 75%, p < 0.0001), especially in viremic subjects, in whom other forms, in addition to 2-LTR circles, may also accumulate due to active viral replication. Indeed, in aviremic On-ART samples, the U-assay unexpectedly measured uDNA in a higher proportion of samples (76%, 22/29) than the 2-LTR assay (41%, 12/29), (p = 0.0164). A trend towards lower uDNA levels was observed in aviremic vs viremic On-ART patients, reaching significance when we combined aviremic On-ART and HIC (controllers) vs Off-ART and viremic On-ART subjects (non-controllers) (p = 0.0003), whereas 2-LTR circle levels remained constant (p ≥ 0.2174). These data were supported by the high correlation found between uDNA and total DNA (r = 0.69, p < 0.001). CONCLUSIONS: The great advantage of the U-assay is that, unlike the 2-LTR assay, it allows the accurate evaluation of the totality of uDNA that can still be measured even during successful ART when plasma viremia is below the cut-off of common clinical tests (< 50 copies/mL) and 2-LTR circles are more likely to be under the quantification limit. UDNA measurement in blood cells may be used as a biomarker to reveal a so far hidden or underestimated viral reservoir. The potential clinical relevance of uDNA quantification may lead to improvements in diagnostic methods to support clinical strategies.

Listeria monocytogenes meningitis in an immunocompromised patient.

This report describes a case of meningitis caused by Listeria monocytogenes in a stem cell transplant recipient on immunosuppressive therapy for cutaneous chronic graft-versus host disease. A 59-year-old woman had undergone allogeneic stem cell transplantation (from a matched unrelated donor) 13 months previously for chronic lymphocytic leukemia. She was on regular hematologic follow-up. Though her previous malignancy has been in remission, she was immunosuppressed due to the pharmacological treatment. We describe a meningitis caused by a typical food-borne pathogen, dangerous in patients with impaired cell-mediated immunity. Moreover the bacterium had a multidrug resistance, a rare characteristic in clinical listeriosis. Rapid diagnosis and treatment are key factors in these cases. We chose ampicillin and rifampicin that allowed a complete resolution of the clinical manifestations.

The Clinical Characteristics of Bloodstream Infections Due to Candida spp. in Patients Hospitalized in Intensive Care Units during the SARS-CoV-2 Pandemic: The Results of a Multicenter Study.

Candidemia is a serious health threat. Whether this infection has a greater incidence and a higher mortality rate in patients with COVID-19 is still debated. In this multicenter, retrospective, observational study, we aimed to identify the clinical characteristics associated with the 30-day mortality in critically ill patients with candidemia and to define the differences in candidemic patients with and without COVID-19. Over a three-year period (2019-2021), we identified 53 critically ill patients with candidemia, 18 of whom (34%) had COVID-19 and were hospitalized in four ICUs. The most frequent comorbidities were cardiovascular (42%), neurological (17%), chronic pulmonary diseases, chronic kidney failure, and solid tumors (13% each). A significantly higher proportion of COVID-19 patients had pneumonia, ARDS, septic shock, and were undergoing an ECMO procedure. On the contrary, non-COVID-19 patients had undergone previous surgeries and had used TPN more frequently. The mortality rate in the overall population was 43%: 39% and 46% in the COVID-19 and non-COVID-19 patients, respectively. The independent risk factors associated with a higher mortality were CVVH (HR 29.08 [CI 95% 3.37-250]) and a Charlson's score of > 3 (HR 9.346 [CI 95% 1.054-82.861]). In conclusion, we demonstrated that candidemia still has a high mortality rate in patients admitted to ICUs, irrespective of infection due to SARS-CoV-2.

Efficacy of bezlotoxumab in preventing the recurrence of Clostridioides difficile infection: an Italian multicenter cohort study.

OBJECTIVES: Bezlotoxumab (BEZ) is a promising tool for preventing the recurrence of Clostridioides difficile infection (rCDI). The aim of the study was to emulate, in a real-world setting, the MODIFY trials in a cohort of participants with multiple risk factors for rCDI treated with BEZ in addition to the standard of care (SoC) versus SoC alone. METHODS: A multicenter cohort study was conducted including 442 patients with Clostridioides difficile infection from 2018 to 2022, collected from 18 Italian centers. The main outcome was the 30-day occurrence of rCDI. The secondary outcomes were (i) all-cause mortality at 30 days (ii) and the composite outcome (30-day recurrence and/or all-cause death). RESULTS: rCDI at day 30 occurred in 54 (12%): 11 in the BEZ + SoC group and 43 treated with SoC alone (8% vs 14%, odds ratio [OR] = 0.58, 95% confidence interval [CI]: 0.31-1.09, P = 0.09). The difference between BEZ + SoC versus SoC was statistically significant after controlling for confounding factors (adjusted OR = 0.40, 95% CI: 018-0.88, P = 0.02) and even more using the composite outcome (adjusted OR = 0.35, 95% CI: 0.17-0.73, P = 0.005). CONCLUSION: Our study confirms the efficacy of BEZ + SoC for the prevention of rCDI and death in a real-world setting. BEZ should be routinely considered among participants at high risk of rCDI regardless of age, type of Clostridioides difficile infection therapy (vancomycin vs fidaxomicin), and number of risk factors.

Antifungal Combinations against Candida Species: From Bench to Bedside.

Candida spp. is the major causative agent of fungal infections in hospitalized patients and the fourth most common cause of nosocomial bloodstream infection (BSI). The availability of standardized methods for testing the in vitro activity of antifungals along with the expanding of antifungal armamentarium, the rising of drug-resistance and the persistence of a high mortality rate in systemic candidiasis have led to an increased interest in combination therapy. Therefore, we aimed to review the scientific literature concerning the antifungal combinations against Candida. A literature search performed in PubMed yielded 92 studies published from 2000 to 2021: 29 articles referring to in vitro studies, six articles referring to either in vitro and in vivo (i.e., animal models) studies and 57 clinical articles. Pre-clinical studies involved 735 isolates of Candida species and 12 unique types of antifungal combination approaches including azoles plus echinocandins (19%), polyenes plus echinocandins (16%), polyenes plus azoles (13%), polyenes plus 5-flucytosine ([5-FC], 13%), azoles plus 5-FC (11%) and other types of combinations (28%). Results varied greatly, often being species-, drug- and methodology-dependent. Some combinatorial regimens exerted a synergistic effect against difficult-to-treat Candida species (i.e., azoles plus echinocandins; polyenes plus 5-FC) or they were more effective than monotherapy in prevent or reducing biofilm formation and in speeding the clearance of infected tissues (i.e., polyenes plus echinocandins). In 283 patients with documented Candida infections (>90% systemic candidiasis/BSI), an antifungal combination approach could be evaluated. Combinations included: azoles plus echinocandins (36%), 5-FC-combination therapies (24%), polyenes plus azoles (18%), polyenes plus echinocandins (16%) and other types of combination therapy (6%). Case reports describing combination therapies yielded favorable response in most cases, including difficult-to-treat fungal infections (i.e., endocarditis, osteoarticular infections, CNS infections) or difficult-to-treat fungal pathogens. The only randomized trial comparing amphotericin-B deoxycholate (AMB) plus FLU vs. AMB alone for treatment of BSI in nonneutropenic patients showed that the combination trended toward improved success and more-rapid clearance from the bloodstream. In summary, antifungal combinations against Candida have produced great interest in the past two decades. To establish whether this approach can become a reliable treatment option, additional in vitro and clinical data are warranted.

Secondary Infections in Critically Ill Patients with COVID-19: A Retrospective Study.

Patients with severe COVID-19, especially those followed in the ICU, are at risk for developing bacterial and fungal superinfections. In this study, we aimed to describe the burden of hospital-acquired superinfections in a cohort of consecutive, severe COVID-19 patients hospitalized between February and May 2021 in the intensive care unit (ICU) department of San Salvatore Hospital in Pesaro, Italy. Among 89 patients considered, 68 (76.4%) acquired a secondary infection during their ICU stay. A total of 46 cases of ventilator-associated pneumonia (VAP), 31 bloodstream infections (BSIs) and 15 catheter-associated urinary tract infections (CAUTIs) were diagnosed. Overall mortality during ICU stay was 48%. A multivariate analysis showed that factors independently associated with mortality were male gender (OR: 4.875, CI: 1.227-19.366, p = 0.024), higher BMI (OR: 4.938, CI:1.356-17.980, p = 0.015) and the presence of VAP (OR: 6.518, CI: 2.178-19.510, p = 0.001). Gram-negative bacteria accounted for most of the isolates (68.8%), followed by Gram-positive bacteria (25.8%) and fungi (5.3%). Over half of the infections (58%) were caused by MDR opportunistic pathogens. Factors that were independently associated with an increased risk of infections caused by an MDR pathogen were higher BMI (OR: 4.378, CI: 1.467-13.064, p = 0.0008) and a higher Charlson Comorbidity Index (OR: 3.451, 95% CI: 1.113-10.700, p = 0.032). Secondary infections represent a common and life-threatening complication in critically ill patients with COVID-19. Efforts to minimize the likelihood of acquiring such infections, often caused by difficult-to-treat MDR organisms-especially in some subgroups of patients with specific risk factors-must be pursued.

In Vitro Activity of Novel Lipopeptides against Triazole-Resistant Aspergillus fumigatus.

Aspergillosis, which is mainly sustained by Aspergillus fumigatus, includes a broad spectrum of diseases. They are usually severe in patients with co-morbidities. The first-line therapy includes triazoles, for which an increasing incidence of drug resistance has been lately described. As a consequence of this, the need for new and alternative antifungal molecules is absolutely necessary. As peptides represent promising antimicrobial molecules, two lipopeptides (C14-NleRR-NH2, C14-WRR-NH2) were tested to assess the antifungal activity against azole-resistant A. fumigatus. Antifungal activity was evaluated by determination of minimum inhibitory concentrations (MICs), time-kill curves, XTT assay, optical microscopy, and checkerboard combination with isavuconazole. Both lipopeptides showed antifungal activity, with MICs ranging from 8 mg/L to 16 mg/L, and a dose-dependent effect was confirmed by both time-kill curves and XTT assays. Microscopy showed that hyphae growth was hampered at concentrations equal to or higher than MICs. The rising antifungal resistance highlights the usefulness of novel compounds to treat severe fungal infections. Although further studies assessing the activity of lipopeptides are necessary, these molecules could be effective antifungal alternatives that overcome the current resistances.

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-week results of a randomized trial.

OBJECTIVES: Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. METHODS: Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm). RESULTS: In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. CONCLUSION: Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therapy.

Prevalence, incidence and clinical outcome of hepatitis B virus and hepatitis C virus hepatitis in patients undergoing allogeneic hematopoietic stem cell transplantation between 2001 and 2004.

The prevalence, incidence and clinical course of viral hepatitis were prospectively determined in consecutive recipients of T-cell depleted hematopoieic stem cell transplants (49 mismatched, 60 matched, mean age 38 years; range 11-65). The prevalence of hepatitis B virus (HBV) was 15.6% and that of hepatitis C virus was 3.7% (HCV). HBV reactivated in one patient. Another developed ex novo acute hepatitis B which progressed to chronic hepatitis. There were no new cases of hepatitis C or worsening of pre-transplant HCV infections. HBV and HBC did not affect the outcome of T-cell depleted hematopoieic stem cell transplantation. Surveillance is important given the risk of HCV and HBV infection and/or reactivation and the efficacy of the new anti-hepatitis drugs.

[Epidemiological, clinical and therapeutical aspects of HIV/HCV coinfection in a series of HIV seropositive Umbrian patients]. / Epidemiologia, clinica e terapia della coinfezione HIV-HCV in una casistica di pazienti umbri.

Because hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share common transmission pathways, HIV-HCV co-infection is frequent, involving about 40% of seropositive subjects particularly injection drug users and patients with hemophilia. We performed a retrospective analysis on clinical, epidemiological and therapeutical aspects in a population of HIV-HCV coinfected patients, observed in our Department during the period 2001-2003. Forty per cent of 404 observed patients had a co-infection; 90% of those were drug addicts and most (90.2%) were on HAART treatment. Seventy-three per cent of co-infected patients showed transaminases alterations, and 85% had detectable viremia. Prevalent genotypes were 1 (44.6%) and 3 (36.4%). The association PEG-IFN and ribavirine obtained sustained responses in 55% of 9 treated patients.

A real time PCR platform for the simultaneous quantification of total and extrachromosomal HIV DNA forms in blood of HIV-1 infected patients.

BACKGROUND: The quantitative measurement of various HIV-1 DNA forms including total, unintegrated and integrated provirus play an increasingly important role in HIV-1 infection monitoring and treatment-related research. We report the development and validation of a SYBR Green real time PCR (TotUFsys platform) for the simultaneous quantification of total and extrachromosomal HIV-1 DNA forms in patients. This innovative technique makes it possible to obtain both measurements in a single PCR run starting from frozen blood employing the same primers and standard curve. Moreover, due to identical amplification efficiency, it allows indirect estimation of integrated level. To specifically detect 2-LTR a qPCR method was also developed. METHODOLOGY/FINDINGS: Primers used for total HIV-1 DNA quantification spanning a highly conserved region were selected and found to detect all HIV-1 clades of group M and the unintegrated forms of the same. A total of 195 samples from HIV-1 patients in a wide range of clinical conditions were analyzed with a 100% success rate, even in patients with suppressed plasma viremia, regardless of CD4+ or therapy. No significant correlation was observed between the two current prognostic markers, CD4+ and plasma viremia, while a moderate or high inverse correlation was found between CD4+ and total HIV DNA, with strong values for unintegrated HIV DNA. CONCLUSIONS/SIGNIFICANCE: Taken together, the results support the use of HIV DNA as another tool, in addition to traditional assays, which can be used to estimate the state of viral infection, the risk of disease progression and to monitor the effects of ART. The TotUFsys platform allowed us to obtain a final result, expressed as the total and unintegrated HIV DNA copy number per microgram of DNA or 10(4) CD4+, for 12 patients within two working days.