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.

Systemic lupus erythematosus and thrombosis.

Systemic Lupus Erythematosus (SLE) is an acquired, multiorgan, autoimmune disease. Clinical presentation is extremely variable and heterogeneous. It has been shown that SLE itself is an independent risk factor for developing both arterial and venous thrombotic events since SLE patients have an Odds Ratio (OR) for thrombosis that varies depending on the clinical and laboratory characteristics of each study cohort. The risk of developing a thrombotic event is higher in this setting than in the general population and may further increase when associated with other risk factors, or in the presence of inherited or acquired pro-thrombotic abnormalities, or trigger events. In particular, a striking increase in the number of thrombotic events was observed when SLE was associated with antiphospholipid antibodies (aPL). The presence of aPLs has been described in about 50% of SLE patients, while about 20% of antiphospholipid syndrome (APS) patients have SLE. While APS patients (with or without an autoimmune disease) have been widely studied in the last years, fewer studies are available for SLE patients and thrombosis in the absence of APS. Although the available literature undoubtedly shows that SLE patients have a greater prevalence of thrombotic events as compared to healthy subjects, it is difficult to obtain a definite result from these studies because in some cases the study cohort was too small, in others it is due to the varied characteristics of the study population, or because of the different (and very copious) laboratory assays and methods that were used. When an SLE patient develops a thrombotic event, it is of great clinical relevance since it is potentially life-threatening. Moreover, it worsens the quality of life and is a clinical challenge for the clinician.

First Human Usutu Virus Reported in Asti (Piedmont, Italy, August 2022) and Early Follow-Up.

The Usutu virus (USUV) has recently attracted the attention of scientists because of its rapid spread across Europe and its growth over the previous seasons in Italy. Here, we describe the first case of USUV infection in Asti, Piedmont region, Italy. The patient remained asymptomatic in the acute phase and during the early follow-up, despite a mild increase in liver enzymes. The prompt diagnosis in this patient was due to positive qualitative PCR for WNV blood-donor screening with negative RT-PCR of WNV and positive USUV-RNA following the confirmation test. Blood-donor screening and transmission risk monitoring are pivotal in following the spread of this Flavivirus in non-endemic countries, due to the high percentage of asymptomatic carriers.

Diagnosis of del(5q) MDS, 14 Years after JAK-2 Positive PV Appearance: Complete Remission of both Diseases with Lenalidomide Monotherapy.

This is the report of the clinical case of a patient who presents the association of a JAK-2 positive chronic myeloproliferative neoplasia to a subsequent 5q- myelodysplastic syndrome, developed after about 14 years from the first diagnosis. Patient's symptoms had rapidly worsened, and she became transfusion-dependent. Therapy with low-dose Lenalidomide quickly reduced the splenomegaly and completely brought white cells counts, haemoglobin, and platelets back to normal. After more than one year from the start, blood cell count is still normal. As far as we know, this is the first case of an effective treatment with Lenalidomide reported in this clinical setting.

Long-term effects of methylprednisolone pulses and mycophenolate mofetil in IgA nephropathy patients at risk of progression.

BACKGROUND: IgA nephropathy (IgAN) is a microcosm of glomerular lesions. Some histologic lesions are irreversible and progress toward obliteration of glomerular capillaries. Others are acute inflammatory processes potentially susceptible to reversal by means of immunosuppressive therapies. METHODS: The effects of a combined schedule of steroids and mycophenolate mofetil (MMF) was prospectively examined in a subset of IgAN patients with acute inflammatory histologic changes associated with proteinuria (mean 2,400 mg/day, range 1,130-5,250), hematuria (76 red cells per high-power microscopic field, range 30-100) and renal failure (serum creatinine 1.6 mg/dL, range 1.2-2.9). Patients had diffuse mesangial proliferation with at least 10% florid crescents, mild to moderate degrees of glomerular sclerosis and interstitial changes, and both mesangial and capillary deposition of immunoreactants at immunofluorescence. Treatment consisted of 3 pulses of methylprednisolone (15 mg/kg) followed by oral prednisone (0.8 mg/kg body weight, tapered until discontinuation within 4 months) and MMF 2 g for 6 months. RESULTS: Serum creatinine, proteinuria and microscopic hematuria significantly dropped at 6 months compared with baseline values (p=0.01) and remained lower at the end of follow-up 51 months (range 24-90) later (p<0.01, for proteinuria and hematuria; p=0.08, for serum creatinine). CONCLUSION: Therapy with steroids and MMF may be considered in a subset of IgAN patients with florid glomerular changes, functional impairment and major urinary abnormalities, to prevent subsequent progression toward renal failure.

Synaptic vesicle docking: sphingosine regulates syntaxin1 interaction with Munc18.

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients.