Convalescent or standard plasma versus standard of care in the treatment of COVID-19 patients with respiratory impairment: short and long-term effects. A three-arm randomized controlled clinical trial.

BACKGROUND: The efficacy of early treatment with convalescent plasma in patients with COVID-19 is debated. Nothing is known about the potential effect of other plasma components other than anti-SARS-CoV-2 antibodies. METHODS: To determine whether convalescent or standard plasma would improve outcomes for adults in early phase of Covid19 respiratory impairment we designed this randomized, three-arms, clinical trial (PLACO COVID) blinded on interventional arms that was conducted from June 2020 to August 2021. It was a multicentric trial at 19 Italian hospitals. We enrolled 180 hospitalized adult patients with COVID-19 pneumonia within 5 days from the onset of respiratory distress. Patients were randomly assigned in a 1:1:1 ratio to standard of care (n = 60) or standard of care + three units of standard plasma (n = 60) or standard of care + three units of high-titre convalescent plasma (n = 60) administered on days 1, 3, 5 after randomization. Primary outcome was 30-days mortality. Secondary outcomes were: incidence of mechanical ventilation or death at day 30, 6-month mortality, proportion of days with mechanical ventilation on total length of hospital stay, IgG anti-SARS-CoV-2 seroconversion, viral clearance from plasma and respiratory tract samples, and variations in Sequential Organ Failure Assessment score. The trial was analysed according to the intention-to-treat principle. RESULTS: 180 patients (133/180 [73.9%] males, mean age 66.6 years [IQR 57-73]) were enrolled a median of 8 days from onset of symptoms. At enrollment, 88.9% of patients showed moderate/severe respiratory failure. 30-days mortality was 20% in Control arm, 23% in Convalescent (risk ratio [RR] 1.13; 95% confidence interval [CI], 0.61-2.13, P = 0.694) and 25% in Standard plasma (RR 1.23; 95%CI, 0.63-2.37, P = 0.544). Time to viral clearance from respiratory tract was 21 days for Convalescent, 28 for Standard plasma and 23 in Control arm but differences were not statistically significant. No differences for other secondary endpoints were seen in the three arms. Serious adverse events were reported in 1.7%, 3.3% and 5% of patients in Control, Standard and Convalescent plasma arms respectively. CONCLUSIONS: Neither high-titer Convalescent nor Standard plasma improve outcomes of COVID-19 patients with acute respiratory failure. Trial Registration Clinicaltrials.gov Identifier: NCT04428021. First posted: 11/06/2020.

Real-life study on the pharmacokinetic of remdesivir in ICU patients admitted for severe COVID-19 pneumonia.

Remdesivir is one of the most encouraging treatments against SARS-CoV-2 infection. After intravenous infusion, RDV is rapidly metabolized (t1/2 = 1 h) within the cells to its active adenosine triphosphate analogue form (GS-443902) and then it can be found in plasma in its nucleoside analogue form (GS-441524). In this real-life study, we describe the remdesivir and GS-441524 concentrations at three time points in nine ICU patients, through a validated ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half-life of GS-441524. The mean Cmin , Cmax and AUC0-24 , were < 0.24 ng/mL and 122.3 ng/mL, 2637.3 ng/mL and 157.8 ng/mL, and 5171.2 ng*h/mL and 3676.5 ng*h/ml, respectively, for RDV and GS-441524. Three out of nine patients achieved a Cmax  > 2610 ng/mL and 140 ng/mL and AUC0-24  > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS-441524, respectively. The mean t1/2 value for GS-441524 was 26.3 h. Despite the low number of patients, these data can represent an interesting preliminary report on the variability of RDV and GS-441524 concentrations in a real-life ICU setting.

Outcome of COVID-19 in liver transplant recipients: A preliminary report from Northwestern Italy.

Covid-19 pandemic is deeply affecting transplant activity worldwide. It is unclear whether solid organ transplant recipients are at increased risk of developing severe complications and how they should be managed, also concerning immunosuppression. This is a report about the course and management of SARS-CoV-2 infection in liver transplant recipients from a single center in Northwestern Italy in the period March-April 2020. Three patients who were treated at our institution are reported in detail, whereas summary data are provided for those managed at peripheral Hospitals. Presentation varied from asymptomatic to rapidly progressive respiratory failure due to bilateral interstitial pneumonia. Accordingly, treatment and changes to immunosuppression were adapted to the severity of the disease. Overall mortality was 20%, whereas Covid-related mortality was 10%. Two cases of prolonged (>2 months) viral carriage were observed in two asymptomatic patients who contracted the infection in the early course after transplant. Besides depicting Covid-19 course and possible treatment scenarios in liver transplant patients, these cases are discussed in relation to the changes in our practice prompted by Covid-19 epidemic, with potential implications for other transplant programs.

CEFTO-CURE study: CEFTObiprole Clinical Use in Real-lifE - a multi-centre experience in Italy.

BACKGROUND: Ceftobiprole is approved in Europe for treatment of community-acquired pneumonia and non-ventilator-associated hospital-acquired pneumonia (HAP) in adults. Real-world data are limited. METHODS: This multi-centre, observational, ambispective investigator-initiated study was undertaken in Italy from January 2018 to December 2019 in order to evaluate the use of ceftobiprole in a real-world setting. RESULTS: Overall, 195 patients from 10 centres were evaluated (68% retrospectively). Male sex was prevalent (n=121, 62%). Median age was 67 [interquartile range (IQR) 53-75] years. Median Charlson Comorbidity Index score was 5 (IQR 3-7). The most common indication was pneumonia (151/195, 77%), especially HAP. Other uses were skin and soft tissue infections (5%), endocarditis (4%) and bone infections (4%). Ceftobiprole was usually an empiric choice (65%), in combination with other drugs (66%) and as second-line therapy (58%). A causative agent was found in 39% of cases. A diagnosis of sepsis was made in 59 cases (30%). Success in the clinically evaluable population (excluding 12 cases due to isolation of pathogens outside ceftobiprole's spectrum of activity) was obtained in 79% of cases, with all-cause mortality of 20%. On multi-level analysis, three predictors were positively associated with clinical success: male gender, pneumonia and detection of causal agent. Sepsis was a negative predictor. Nine factors were independently associated, favourably or unfavourably, with fatal outcome. CONCLUSIONS: Ceftobiprole is a safe and effective therapeutic choice, even in a real-world setting. More data are needed to establish its efficacy in patients with sepsis.

Testosterone as a Biomarker of Adverse Clinical Outcomes in SARS-CoV-2 Pneumonia.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may affect testicles. Lower testosterone levels have been associated with worse clinical outcomes and higher mortality. Our objective was to evaluate the hypothalamic−pituitary−gonadal axis of men admitted with SARS-CoV-2 pneumonia and its link with the pneumonia-treatment intensification. Short-term changes in hormonal parameters were also assessed. Methods: Men admitted with SARS-CoV-2 pneumonia were recruited in two different hospitals in Piedmont, Italy. In all patients, the assessment of total testosterone (TT), calculated free testosterone (cFT), gonadotropins, inhibin B (InhB), and other biochemical evaluations were performed at admission (T0) and before discharge (T1). Through a review of medical records, clinical history was recorded, including data on pneumonia severity. Results: Thirty-five men (median age 64 [58−74] years) were recruited. Lower TT and cFT levels at T0 were associated with CPAP therapy (p = 0.045 and 0.028, respectively), even after adjusting for age and PaO2/FIO2 ratio in a multivariable analysis. In those discharged alive, lower TT and cFT levels were associated with longer hospital stay (p < 0.01). TT, cFT, and InhB were below the normal range at T0 and significantly increased at T1 (TT 1.98 [1.30−2.72] vs. 2.53 [1.28−3.37] ng/mL, p = 0.038; cFT (0.0441 [0.0256−0.0742] vs. 0.0702 [0.0314−0.0778] ng/mL, p = 0.046; InhB 60.75 [25.35−88.02] vs. 77.05 [51.15−134.50], p < 0.01). Conclusions: Both TT and cFT levels are associated with adverse clinical outcomes in men admitted with SARS-CoV-2 pneumonia. As TT, cFT and InhB levels increase before discharge, short-term functional recovery of steroidogenesis and an indirect improvement of spermatozoa functional status could be hypothesized.

Klebsiella pneumoniae meningitis in a 38-year-old Chinese traveller with impaired glucose tolerance: a new emerging syndrome?

Early diagnosis and appropriate empirical treatment of bacterial meningitis reduce morbidity and mortality. Prevalence rates of different causative pathogens associated with bacterial meningitis can depend on age, the underlying medical condition, way of infection and geographical distribution. Klebsiella pneumoniae represents an infrequent cause of community-acquired meningitis in South-East Asia and North-East Asia, where it accounts for 20% of all bacterial meningitis, frequently associated with septic metastatic complications. We describe a case of K. pneumoniae meningitis, diplopia and chemosis in a recently immigrated patient with impaired glucose tolerance. The reason for the high prevalence of metastatic septic infections caused by K. pneumoniae in Taiwan and South-East Asia remains unclear: high prevalence in this area of serotype K1 and K2 and the expression of a novel locus called magA conferring to bacterium an elevated phagocytosis resistance and an active proliferation ability have been suggested. A high degree of suspicion for this etiology must be taken into account in immigrants from China and Taiwan. Due to a very high lethality, guidelines on empiric treatment should be considered in the management of bacterial meningitis, with the patients geographical origin and the clinical syndrome (meningitis and endophtalmitis) as potential risk factors for K. pneumoniae infection.

[Primary soft tissue and tenosynovial tuberculosis after needlestick injury in a surgeon]. / Tubercolosi primaria tenosinoviale e dei tessuti molli da inoculazione in un chirurgo.

We describe the case of a surgeon, who pricked himself with a needle used to drain a paravertebral abscess in a patient from Sudan. He lost this patient at follow up. Six weeks later, the surgeon developed oedema of his left hand and wrist. He started antibiotics, amoxicillin/clavulanate plus ciprofloxacin 2 weeks, without any improvement. He came to our centre for examination, and by chance his patient had been admitted to our ward the day before, and had died during the night of disseminated tuberculosis. The surgeon was treated with rifampin, isoniazid and pyrazinamide (3 drugs 2 months, followed by rifampin plus isoniazid for further 7 months) with rapid improvement. He could start his job again after 5 months. To our knowledge, this is the first case of inoculation tuberculosis transmitted to a surgeon, while other cases in health care workers (internists, pathologists, nurses...) have already been well described.

Prevalence of pfcrt point mutations and level of chloroquine resistance in Plasmodium falciparum isolates from Africa.

The development in Plasmodium falciparum of the resistance to chloroquine (CQ) constitutes a public health priority, due to its direct influence in childhood mortality. The molecular basis for CQ resistance (CQR) is still unclear but, recently, a new relevant gene, named pfcrt, with several point mutations was identified in P. falciparum. Two mutations, K76T and A220S, have been considered crucial for CQR in further studies, making the pfcrt a good candidate as determinant for CQR in P. falciparum. To contribute to this topic, we have undertaken a molecular screening on 164 P. falciparum isolates from Africa: 120 isolates were Italian imported malaria cases, 27 and 17 isolates were from a school-children survey from Congo and Tanzania, respectively. In vitro tests (pLDH and WHO-Mark III tests) for CQ sensitivity have been also carried out on 28 plasmodial isolates and results compared to those obtained by molecular analysis in the same isolates. The SVIET pfcrt haplotype has been identified in the samples from Congo, and this is the first time that this haplotype is detected in Africa. Our results give further evidence to the reliability of the 76T (and the linked 74I-75E) pfcrt point mutation as molecular marker for CQR.

Chemosusceptibility analysis of Plasmodium falciparum imported malaria in Italy.

A constant surveillance of susceptibility to antimalarials allows to optimize prevention and treatment of malaria in nonendemic countries. In vitro susceptibility of imported Plasmodium falciparum isolates to chloroquine, quinine, mefloquine, halofantrin, pyronaridine, and amodiaquine was analyzed by WHO Micro-test Mark III; IC50 and IC90 were calculated by WHO Log-probit. Sixty-seven tests were performed. All the infections were acquired in Africa: 14.9% in East Africa and 85.1% in West Africa (WA). IC50 and IC90 (micromol/L) were chloroquine: 0.129 and 0.648; amodiaquine: 1.134 and 5.445; mefloquine: 0.38 and 0.868; quinine: 0.193 and 0.478; halofantrin: 3.27 and 25.35; pyronaridine: 11.504 and 51.996. Higher IC50 and IC90 were observed in East Africa versus West Africa strains. All strains were susceptible to quinine and mefloquine; chloroquine resistance, 14%; amodiaquine resistance, 33%, with cross-resistance to chloroquine (r = 0.93; P < .0001); halofantrin resistance, 3.6%, no cross-resistance with chloroquine; low susceptibility to pyronaridine (66.7%), with cross-resistance with chloroquine (r = 0.38, P < 0.05). Lower levels of chloroquine resistance were observed in 2000-2003 as compared with prior data; thus, the reemergence of chloroquine susceptibility in Africa may be hypothesized.

Pharmacodynamic analysis of antimalarials used in Plasmodium falciparum imported malaria in northern Italy.

BACKGROUND: Conventional treatment of imported malaria in Italy consists of quinine or mefloquine. Since beta-arthemeter is now available, an open-label pharmacodynamic analysis was performed in 73 adults with uncomplicated Plasmodium falciparum malaria. In vitro susceptibility to mefloquine and quinine was evaluated at admission. METHODS: According to clinical status, baseline parasitemia (P(0)), and premunition, the patients received intravenous quinine, oral mefloquine, or beta-arthemeter. The following parameters were measured: parasitemia at 0, 6, 12, and 24 hours and then every 24 hours until negative; time to 50%, 90%, and 100% reduction in parasite density (PC(50), PC(90), and PCT); parasite reduction ratio at 24 and 48 hours (PRR(24) and PRR(48)); percentage of patients with undetectable parasitemia at 48 hours (PPUP(48)); time required to eradication; in vitro susceptibility to mefloquine and quinine by World Health Organization Microtest Mark III. RESULTS: Of the study patients, 54.8% were immigrants from malaria-endemic countries. All the infections were acquired in Africa. All the patients were treated successfully. According to the pharmacodynamic parameters measured, no significant differences were recorded among patients with or without prior exposure to malaria. Pharmacodynamic comparison was performed between quinine and beta-arthemeter. Significantly higher clearance times were recorded for beta-arthemeter vs quinine (PC(50), PC(90), and PCT: 16.8, 42.6, and 72 h for quinine vs 7.9, 12.2, and 48 h for beta-arthemeter; p values: .02, < .0001, and .008, respectively). The number of patients who obtained a PPUP(48) with beta-arthemeter was higher than with quinine (66.7 vs 9.1%, p < .003), and PRR(24) was significantly higher in beta-arthemeter-treated patients (617 vs 3.15, p = .0001). PRR(48) and time to eradication were not measurable in the beta-arthemeter group (negative P at 48 h in most cases). Two recrudescences occurred after 5 and 7 days of beta-arthemeter monotherapy. All strains were fully susceptible to quinine and mefloquine. CONCLUSIONS: Pharmacodynamic properties of mefloquine and quinine are in the range reported in literature. The better PCT and pharmacodynamics of beta-arthemeter suggest that it could be used as a first-line agent, coadministered with mefloquine.

Clinical epidemiology in Italian Registry of Infective Endocarditis (RIEI): Focus on age, intravascular devices and enterococci.

INTRODUCTION: The epidemiology of infective endocarditis (IE) is changing due to a number of factors, including aging and health related comorbidities and medical procedures. The aim of this study is to describe the main clinical, epidemiologic and etiologic changes of IE from a large database in Italy. METHODS: We prospectively collected episodes of IE in 17 Italian centers from July 2007 to December 2010. RESULTS: We enrolled 677 patients with definite IE, of which 24% health-care associated. Patients were male (73%) with a median age of 62 years (IQR: 49-74) and 61% had several comorbidities. One hundred and twenty-eight (19%) patients had prosthetic left side IE, 391 (58%) native left side IE, 94 (14%) device-related IE and 54 (8%) right side IE. A predisposing cardiopathy was present in 50%, while odontoiatric and non odontoiatric procedures were reported in 5% and 21% of patients respectively. Symptoms were usually atypical and precocious. The prevalent etiology was represented by Staphylococcus aureus (27%) followed by coagulase-negative staphylococci (CNS, 21%), Streptococcus viridans (15%) and enterococci (14%). CNS and enterococci were relatively more frequent in patients with intravascular devices and prosthesis and S. viridans in left native valve. Diagnosis was made by transthoracic and transesophageal echocardiography in 62% and 94% of cases, respectively. The in-hospital mortality was 14% and 1-year mortality was 21%. CONCLUSION: The epidemiology is changing in Italy, where IE more often affects older patients with comorbidities and intravascular devices, with an acute onset and including a high frequency of enterococci. There were few preceding odontoiatric procedures.

Puumala virus pulmonary syndrome in a Romanian immigrant.

Hantaviruses belong to the Bunyaviridae family, which is comprised of Bunyavirus, Phlebovirus, Nairovirus, and Hantavirus. Euroasiatic Hantaviruses belong to two distinct subfamilies: Murinae (comprising Hantaan, Dobrava, and Seoul viruses), which are responsible for hemorrhagic fever with renal syndrome (HFRS), and Arvicolinae (comprising Puumala virus), responsible for nephropathia epidemica (NE) and HFRS. On the contrary, the New World Hantavirus belongs to the Sigmodontinae subfamily and includes the North American viruses: Sin Nombre, Monongahela; New York, Bayou, Black Creek Canal, and the South American, which comprise the Andes, Oran, Lechiguanas, Laguna Negra, Juquitiba; both groups are responsible for the hantavirus pulmonary syndrome (HPS).

Resolution of HCV infection after highly active antiretroviral therapy in a HIV-HCV coinfected patient.

The effect of HAART on HCV infection and HCV-RNA plasma levels is controversial. We describe a patient with HIV-HCV coinfection with persistent disappearance of HCV-RNA after immunological and virological response to HAART, and we briefly discuss similar cases reported in the literature.